Genetics of Prostate Cancer (PDQ®): Genetics - Health Professional Information [NCI]

Executive Summary

This executive summary reviews the topics covered in this PDQ summary on the genetics of prostate cancer, with hyperlinks to detailed sections below that describe the evidence on each topic.

• Inheritance and Risk

  A genetic contribution to prostate cancer risk has been documented, and knowledge about the molecular genetics of the disease is increasing. Clinical management based on knowledge of inherited pathogenic variants is emerging. Factors suggestive of a genetic contribution to prostate cancer include the following: 1) multiple affected first-degree relatives (FDRs) with prostate cancer, including three successive generations with prostate cancer in the maternal or paternal lineage; 2) early-onset prostate cancer (age ≤55 y); and 3) prostate cancer with a family history of other cancers (e.g., breast, ovarian, pancreatic).

• Associated Genes and Single Nucleotide Variants (SNVs)

  Several genes and chromosomal regions have been found to be associated with prostate cancer in various linkage analyses, case-control studies, genome-wide association studies (GWAS), next-generation sequencing (NGS), and admixture mapping studies. Pathogenic variants in genes, such as BRCA1, BRCA2, the mismatch repair genes, and HOXB13 confer modest to moderate lifetime risk of prostate cancer. Some, such as BRCA2, have emerging clinical relevance in the treatment and screening for prostate cancer. In addition, GWAS have identified more than 150 SNVs associated with the development of prostate cancer, but the clinical utility of these findings remains uncertain. Studies are ongoing to assess whether combinations of these SNVs (e.g., polygenic risk scores) may have clinical relevance in identifying individuals at increased risk of the disease. Studies analyzing the association between variants and aggressive disease are also ongoing.

• Clinical Management

  Information is limited about the efficacy of commonly available screening tests such as the digital rectal exam and serum prostate-specific antigen (PSA) levels in men genetically predisposed to developing prostate cancer. Initial reports of targeted PSA screening of carriers of BRCA pathogenic variants has yielded a higher proportion of aggressive disease. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. For example, some experts suggest initiating prostate cancer screening at age 40 years in carriers of BRCA2 pathogenic variants and consideration of screening in BRCA1 carriers. Inherited variants may influence treatment decisions, particularly for males with pathogenic variants in DNA repair genes. Studies have reported improved response rates to poly (ADP-ribose) polymerase (PARP) inhibition and platinum-based chemotherapy among males with metastatic, castrate-resistant prostate cancer carrying germline pathogenic variants in BRCA2 and other DNA repair genes.

• Psychosocial and Behavioral Issues

  Psychosocial research in men at increased hereditary risk of prostate cancer has focused on risk perception, interest in genetic testing, and screening behaviors. Study conclusions vary regarding whether FDRs of prostate cancer patients accurately estimate their prostate cancer risk, with some studies reporting that men with a family history of prostate cancer consider their risk to be the same as or less than that of the average man. Factors such as being married and the confusion between benign prostatic hyperplasia and prostate cancer have been found to influence perceived risk of prostate cancer. Studies conducted before the availability of genetic testing for prostate cancer susceptibility showed that factors found to positively influence men's hypothetical interest in genetic testing included the advice of their primary care physician, a combination of the emotional distress and concern about prostate cancer treatment effects, and having children. Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk based on family history; in general, results appear contradictory regarding whether men with a family history are more likely to be screened than those not at risk and whether the screening is appropriate for their risk status. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.

Introduction

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. For more information, see OMIM.

A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term "variant" rather than the term "mutation" to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. For more information on variant classification, see Cancer Genetics Overview.

The public health burden of prostate cancer is substantial. A total of 268,490 new cases of prostate cancer and 34,500 deaths from the disease are anticipated in the United States in 2022, making it the most frequent nondermatological cancer among U.S. males.[1] A man's lifetime risk of prostate cancer is one in eight. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] In an analysis of 58 autopsy studies, the estimated number of men globally with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patient's life) varied by race.[3] A 50% prevalence of latent prostate cancer was found by age 60 years in men of African descent, age 80 years in White men, and age 90 years in Asian men.[3] A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the annual incidence rate of prostate cancer in different regions in the world ranges from 86.4 cases per 100,000 men in Australia and New Zealand to 5.0 cases per 100,000 men in South Central Asia.[4] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 5.0 to 13.9 cases per 100,000 men. The highest incidence rates are generally observed in Australia and New Zealand (86.4 cases/100,000 men), Northern European countries (85.7 cases/100,000 men), Western European countries (75.8 cases/100,000 men), and North American countries (73.7 cases/100,000 men).[4] Non-Hispanic Black men in the United States, however, have the highest incidence of prostate cancer in the world (172.6 cases/100,000 men).[1] Globally, lower prostate cancer incidences are observed in African countries (Northern African countries, 13.2 cases/100,000 men; Eastern African countries, 23.9 cases/100,000 men; Western African countries, 31.9 cases/100,000 men; and Middle African countries, 35.9 cases/100,000 men).[4] Within the United States, non-Hispanic Black men have an almost 80% higher incidence rate than non-Hispanic White men.[1] Non-Hispanic Black men have been reported to have more than twice the rate of prostate cancer–specific death (37.9/100,000 men) when compared with non-Hispanic White men (17.8/100,000 men).[1]

These differences may be due in part to environmental and social influences (such as access to health care), which may affect the development and progression of the disease.[5,6] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[7] This may be attributed to an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, and there is increasing knowledge of the molecular genetics of the disease, although much of what is known is not yet clinically actionable. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[8,9,10]

Risk Factors for Prostate Cancer

The four most important recognized risk factors for prostate cancer in the United States are:

• Age.
• Ancestry.
• Family cancer history.
• Germline genetic variants.

Age

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 456 for men 49 years or younger, 1 in 54 for men aged 50 through 59 years, 1 in 19 for men aged 60 through 69 years, and 1 in 11 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 8.[1]

Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer is increasing, and there is evidence that some cases may be more aggressive.[11] There is a worldwide trend toward an increase in the number of men younger than 40 years diagnosed with prostate cancer, often with poor prognoses.[12] Because early-onset cancers may result from germline pathogenic variants, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.

Ancestry

The risk of developing prostate cancer is dramatically higher among non-Hispanic Black individuals (172.6 cases/100,000 men) when compared with other racial groups in the United States (non-Hispanic White, 99.9 cases/100,000 men; Asian or Pacific Islander, 55.0 cases/100,000 men; American Indian or Alaska Native, 79.8 cases/100,000 men; and Hispanic or Latino, 85.3 cases/100,000 men).[1] Prostate cancer mortality rates in non-Hispanic Black individuals (37.9/100,000 men) are also more than double those of other racial groups in the United States (non-Hispanic White, 17.8/100,000 men; Asian or Pacific Islander, 8.6/100,000 men; American Indian or Alaska Native, 21.0/100,000 men; and Hispanic or Latino, 15.6/100,000 men).[1] Globally, prostate cancer incidence and mortality rates also vary widely country to country.[4] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[5,6]

Family cancer history

Prostate cancer is highly heritable; the inherited risk of prostate cancer has been estimated to be as high as 60%. As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[13,14,15,16,17] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[14,18,19] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[15,16,17,18,19] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[20]

Although some of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[21,22,23] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. For a summary of relative risks (RRs) that are associated with a family history of prostate cancer, see Table 1.[24]

Table 1. Relative Risk (RR) Related to Family History of Prostate Cancer^a

Risk Group	RR for Prostate Cancer (95% CI)
CI = confidence interval; FDR = first-degree relative.
a Adapted from Kiciński et al.[24]
Brother(s) with prostate cancer diagnosed at any age	3.14 (2.37–4.15)
Father with prostate cancer diagnosed at any age	2.35 (2.02–2.72)
One affected FDR diagnosed at any age	2.48 (2.25–2.74)
Affected FDRs diagnosed <65 y	2.87 (2.21–3.74)
Affected FDRs diagnosed ≥65 y	1.92 (1.49–2.47)
Second-degree relativesdiagnosed at any age	2.52 (0.99–6.46)
Two or more affected FDRs diagnosed at any age	4.39 (2.61–7.39)

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[25] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% confidence interval [CI], 2.05–2.20) with an affected father only, 2.96 (95% CI, 2.80–3.13) with an affected brother only, and 8.51 (95% CI, 6.13–11.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.26–25.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[26] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

A family history of breast cancer is also associated with increased prostate cancer risk. In the Health Professionals Follow-up Study (HPFS), comprising over 40,000 men, those with a family history of breast cancer had a 21% higher risk of developing prostate cancer overall and a 34% increased risk of developing a lethal form of prostate cancer.[27] This is consistent with findings from previous cohorts,[22] though, notably, not all series have detected this association.[21,28] The HPFS and other studies have also shown that men with a family history of both prostate and breast/ovarian cancers were at an even higher risk of prostate cancer compared with men with a family history of either prostate or breast/ovarian cancer alone.[21,27] A proportion of the increased prostate cancer risk associated with family history of breast cancer is likely due to pathogenic variants in the DNA damage repair pathway, most commonly BRCA2.[29,30,31,32] For more information, see the BRCA1 and BRCA2 section. The association between prostate and breast cancers in families appears bidirectional. Among women, a family history of prostate cancer is likewise associated with increased risk of breast cancer.[33,34]

An association also exists between prostate cancer risk and colon cancer. Men with germline variants in DNA mismatch repair genes are at increased risk of developing prostate cancer.[35] One study reported an approximately twofold increased risk of prostate cancer among first- and second-degree relatives of probands with colorectal cancer meeting Amsterdam I or Amsterdam II criteria for Lynch syndrome.[36] For more information on Amsterdam criteria, see the Defining Lynch syndrome families section in Genetics of Colorectal Cancer.

Prostate cancer clusters with particular intensity in some families. Highly to moderately penetrant genetic variants are thought to be associated with prostate cancer risk in these families. Members of these families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on an individual's age at prostate cancer diagnosis, prostate cancer stage at diagnosis, and specific patterns of cancer in the family history.[37,38] For more information about genetic testing criteria for prostate cancer, see Table 2.

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African American, White, and Asian American individuals in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[39] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian American individuals than among African American or White individuals. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio (OR) associated with a family history of prostate cancer was 2.5 (95% CI, 1.9–3.3) with adjustment for age and ethnicity.[39]

There is variable evidence that family history alone is associated with inferior clinical outcomes. In a cohort of 7,690 men in Germany who were undergoing radical prostatectomy for localized prostate cancer, family history had no bearing on prostate cancer–specific survival.[40] A large population-based study from Utah reported that family history meeting criteria for hereditary prostate cancer was associated with increased risk of prostate cancer overall (RR, 2.30; 95% CI, 2.22–2.40), early-onset prostate cancer (RR, 3.93; 95% CI, 3.33–4.61), lethal disease (RR, 2.21; 95% CI, 1.95–2.50), and clinically significant disease (RR, 2.32; 95% CI, 2.17–2.48).[41] Furthermore, family history meeting criteria for hereditary breast and ovarian cancer syndrome was associated with increased risk of prostate cancer overall (RR, 1.47; 95% CI, 1.43–1.50), early-onset disease (RR, 2.05; 95% CI, 1.86–2.25), lethal disease (RR, 1.39; 95% CI, 1.30–1.50), and clinically significant disease (RR, 1.47; 95% CI, 1.42–1.53). Family history meeting criteria for Lynch syndrome in this study was associated with increased prostate cancer risks, though to a lesser extent: prostate cancer overall (RR, 1.16; 95% CI, 1.12–1.19), early-onset disease (RR, 1.34; 95% CI, 1.18–1.52), and clinically significant disease (RR ,1.15; 95% CI, 1.10–1.21).

Germline genetic variants

There are multiple germline pathogenic variants and single nucleotide variants across the genome that are associated with prostate cancer risk. For more information about these genetic variants, see the National Human Genome Research Institute GWAS catalog, and for information about prostate cancer genetic testing, see the Clinical Application of Genetic Testing for Inherited Prostate Cancer section.

Multiple Primaries

The SEER Cancer Registries assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 15.0%–15.4%). There was a significant risk of new malignancies (all cancers combined) among men diagnosed before age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus; and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer, which may relate to the inheritance of pathogenic variants in BRCA1/BRCA2.[42]

A review of more than 441,000 men diagnosed with prostate cancer between 1992 and 2010 demonstrated similar findings, with an overall reduction in the risk of being diagnosed with a second primary cancer. This study also examined the risk of second primary cancers in 44,310 men (10%) by treatment modality for localized cancer. The study suggested that men who received radiation therapy had increases in bladder (standardized incidence ratio [SIR], 1.42) and rectal cancer risk (SIR, 1.70) compared with those who did not receive radiation therapy (SIR_bladder, 0.76; SIR_rectal, 0.74).[43]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 80,449 men with prostate cancer, 6,396 developed a second primary malignancy. Those with a family history of cancer were found to have an increased risk for a second primary cancer with the greatest risk consisting of colorectal cancer (RR, 1.78; 95% CI, 1.56–1.90), lung cancer (RR, 2.29; 95% CI, 1.65–3.18), kidney cancer (RR, 3.59; 95% CI, 1.61–7.99), bladder cancer (RR, 3.84; 95% CI, 2.63–5.60), melanoma (RR, 2.30; 95% CI, 1.86–2.93), squamous cell skin cancer (RR, 2.10; 95% CI, 1.92–2.26), and leukemia (RR, 3.88; 95% CI, 1.94–7.77). Among probands with prostate cancer with a family history of cancer, 47% of deaths were secondary to a second primary malignancy. The cumulative incidence of a second primary cancer by age 83 years was highest (35%) in those participants with a family history of cancer in contrast to those without a family history of cancer (28%).[44]

Data are emerging that prostate cancer patients who have at least one additional primary malignancy disproportionately harbor pathogenic variants in known cancer-predisposing genes, such as BRCA2 and MLH1.[45]

Risk of Other Cancers in Multiple-Case Families

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[46,47,48]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (SIR, 1.9; 95% CI, 1.0–3.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer site–specific disorder.[49]

A study from the Swedish Family Cancer Database reported an increased risk of the following cancers in families where multiple members had a prostate cancer diagnosis: myeloma (RR, 2.44; 95% CI, 1.24–4.82), kidney cancer (RR, 2.32; 95% CI, 1.23–4.36), nonthyroid endocrine tumors (RR, 2.18; 95% CI, 1.06–4.49), melanoma (RR, 1.82; 95% CI, 1.18–2.80), nervous system tumors (RR, 1.77; 95% CI, 1.08–2.91), and female breast cancer (RR, 1.37; 95% CI, 1.02–1.86).[50] It remains to be determined whether these associations are from a common genetic basis, shared environment, or a combination of factors.

Inheritance of Prostate Cancer Risk

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic (MZ) and dizygotic (DZ) twin pairs in Scandinavia concluded that 58% (95% CI, 52%–63%) of prostate cancer risk may be accounted for by heritable factors.[9] Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins (mean, 3.8 y in MZ twins vs. 6.5 y in DZ twins). This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs.[51] A Swedish study also found concordance with disease aggressiveness defined as Gleason score greater than 6, clinical stage greater than T2, N1, M1, and PSA greater than 10 (OR, 3.82 for MZ twins [95% CI, 0.99–16.72]; OR, 1.38 for DZ twins [95% CI, 0.27–7.29]; and OR, 1.21 for full brothers [95% CI, 1.04–1.39]).[10]

The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency, 0.003) autosomal dominant, highly penetrant allele(s).[14] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 y or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[52]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[53,54,55] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[51] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [56,57,58,59] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (<66 y) than noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[60]

References:

1. American Cancer Society: Cancer Facts and Figures 2022. American Cancer Society, 2022. Available online. Last accessed October 7, 2022.
2. Ruijter E, van de Kaa C, Miller G, et al.: Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 20 (1): 22-45, 1999.
3. Rebbeck TR, Haas GP: Temporal trends and racial disparities in global prostate cancer prevalence. Can J Urol 21 (5): 7496-506, 2014.
4. Bray F, Ferlay J, Soerjomataram I, et al.: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68 (6): 394-424, 2018.
5. Krimphove MJ, Cole AP, Fletcher SA, et al.: Evaluation of the contribution of demographics, access to health care, treatment, and tumor characteristics to racial differences in survival of advanced prostate cancer. Prostate Cancer Prostatic Dis 22 (1): 125-136, 2019.
6. Fletcher SA, Marchese M, Cole AP, et al.: Geographic Distribution of Racial Differences in Prostate Cancer Mortality. JAMA Netw Open 3 (3): e201839, 2020.
7. Hemminki K, Rawal R, Bermejo JL: Prostate cancer screening, changing age-specific incidence trends and implications on familial risk. Int J Cancer 113 (2): 312-5, 2005.
8. Packer JR, Maitland NJ: The molecular and cellular origin of human prostate cancer. Biochim Biophys Acta 1863 (6 Pt A): 1238-60, 2016.
9. Hjelmborg JB, Scheike T, Holst K, et al.: The heritability of prostate cancer in the Nordic Twin Study of Cancer. Cancer Epidemiol Biomarkers Prev 23 (11): 2303-10, 2014.
10. Jansson F, Drevin L, Frisell T, et al.: Concordance of Non-Low-Risk Disease Among Pairs of Brothers With Prostate Cancer. J Clin Oncol 36 (18): 1847-1852, 2018.
11. Salinas CA, Tsodikov A, Ishak-Howard M, et al.: Prostate cancer in young men: an important clinical entity. Nat Rev Urol 11 (6): 317-23, 2014.
12. Bleyer A, Spreafico F, Barr R: Prostate cancer in young men: An emerging young adult and older adolescent challenge. Cancer 126 (1): 46-57, 2020.
13. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990.
14. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.
15. Ghadirian P, Howe GR, Hislop TG, et al.: Family history of prostate cancer: a multi-center case-control study in Canada. Int J Cancer 70 (6): 679-81, 1997.
16. Stanford JL, Ostrander EA: Familial prostate cancer. Epidemiol Rev 23 (1): 19-23, 2001.
17. Matikaine MP, Pukkala E, Schleutker J, et al.: Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland. Cancer Causes Control 12 (3): 223-30, 2001.
18. Grönberg H, Damber L, Damber JE: Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 77 (1): 138-43, 1996.
19. Cannon L, Bishop DT, Skolnick M, et al.: Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1 (1): 47-69, 1982.
20. Bratt O, Garmo H, Adolfsson J, et al.: Effects of prostate-specific antigen testing on familial prostate cancer risk estimates. J Natl Cancer Inst 102 (17): 1336-43, 2010.
21. Kalish LA, McDougal WS, McKinlay JB: Family history and the risk of prostate cancer. Urology 56 (5): 803-6, 2000.
22. Cerhan JR, Parker AS, Putnam SD, et al.: Family history and prostate cancer risk in a population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 8 (1): 53-60, 1999.
23. Albright F, Stephenson RA, Agarwal N, et al.: Prostate cancer risk prediction based on complete prostate cancer family history. Prostate 75 (4): 390-8, 2015.
24. Kiciński M, Vangronsveld J, Nawrot TS: An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One 6 (10): e27130, 2011.
25. Brandt A, Bermejo JL, Sundquist J, et al.: Age-specific risk of incident prostate cancer and risk of death from prostate cancer defined by the number of affected family members. Eur Urol 58 (2): 275-80, 2010.
26. Grönberg H, Wiklund F, Damber JE: Age specific risks of familial prostate carcinoma: a basis for screening recommendations in high risk populations. Cancer 86 (3): 477-83, 1999.
27. Barber L, Gerke T, Markt SC, et al.: Family History of Breast or Prostate Cancer and Prostate Cancer Risk. Clin Cancer Res 24 (23): 5910-5917, 2018.
28. Damber L, Grönberg H, Damber JE: Familial prostate cancer and possible associated malignancies: nation-wide register cohort study in Sweden. Int J Cancer 78 (3): 293-7, 1998.
29. Agalliu I, Karlins E, Kwon EM, et al.: Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer 97 (6): 826-31, 2007.
30. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003.
31. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.
32. Gayther SA, de Foy KA, Harrington P, et al.: The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 60 (16): 4513-8, 2000.
33. Beebe-Dimmer JL, Yee C, Cote ML, et al.: Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women's Health Initiative Study. Cancer 121 (8): 1265-72, 2015.
34. Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994.
35. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al.: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22 (1): 15-25, 2020.
36. Samadder NJ, Smith KR, Wong J, et al.: Cancer Risk in Families Fulfilling the Amsterdam Criteria for Lynch Syndrome. JAMA Oncol 3 (12): 1697-1701, 2017.
37. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015.
38. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed March 1, 2023.
39. Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995.
40. Brath JM, Grill S, Ankerst DP, et al.: No Detrimental Effect of a Positive Family History on Long-Term Outcomes Following Radical Prostatectomy. J Urol 195 (2): 343-8, 2016.
41. Beebe-Dimmer JL, Kapron AL, Fraser AM, et al.: Risk of Prostate Cancer Associated With Familial and Hereditary Cancer Syndromes. J Clin Oncol 38 (16): 1807-1813, 2020.
42. McMaster ML, Feuer EJ, Tucker MA: New malignancies following cancer of the male genital tract. In: Curtis RE, Freedman DM, Ron E, et al., eds.: New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973-2000. National Cancer Institute, 2006. NIH Pub. No. 05-5302, pp 257-84.
43. Davis EJ, Beebe-Dimmer JL, Yee CL, et al.: Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study. Cancer 120 (17): 2735-41, 2014.
44. Chattopadhyay S, Hemminki O, Försti A, et al.: Impact of family history of cancer on risk and mortality of second cancers in patients with prostate cancer. Prostate Cancer Prostatic Dis 22 (1): 143-149, 2019.
45. Pilié PG, Johnson AM, Hanson KL, et al.: Germline genetic variants in men with prostate cancer and one or more additional cancers. Cancer 123 (20): 3925-3932, 2017.
46. Isaacs SD, Kiemeney LA, Baffoe-Bonnie A, et al.: Risk of cancer in relatives of prostate cancer probands. J Natl Cancer Inst 87 (13): 991-6, 1995.
47. Albright LA, Schwab A, Camp NJ, et al.: Population-based risk assessment for other cancers in relatives of hereditary prostate cancer (HPC) cases. Prostate 64 (4): 347-55, 2005.
48. Grönberg H, Bergh A, Damber JE, et al.: Cancer risk in families with hereditary prostate carcinoma. Cancer 89 (6): 1315-21, 2000.
49. Pakkanen S, Pukkala E, Kainulainen H, et al.: Incidence of cancer in finnish families with clinically aggressive and nonaggressive prostate cancer. Cancer Epidemiol Biomarkers Prev 18 (11): 3049-56, 2009.
50. Frank C, Sundquist J, Hemminki A, et al.: Familial Associations Between Prostate Cancer and Other Cancers. Eur Urol 71 (2): 162-165, 2017.
51. Page WF, Braun MM, Partin AW, et al.: Heredity and prostate cancer: a study of World War II veteran twins. Prostate 33 (4): 240-5, 1997.
52. Lange EM, Salinas CA, Zuhlke KA, et al.: Early onset prostate cancer has a significant genetic component. Prostate 72 (2): 147-56, 2012.
53. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998.
54. Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997.
55. Verhage BA, Baffoe-Bonnie AB, Baglietto L, et al.: Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology 57 (1): 97-101, 2001.
56. Gong G, Oakley-Girvan I, Wu AH, et al.: Segregation analysis of prostate cancer in 1,719 white, African-American and Asian-American families in the United States and Canada. Cancer Causes Control 13 (5): 471-82, 2002.
57. Cui J, Staples MP, Hopper JL, et al.: Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am J Hum Genet 68 (5): 1207-18, 2001.
58. Conlon EM, Goode EL, Gibbs M, et al.: Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset. Int J Cancer 105 (5): 630-5, 2003.
59. Valeri A, Briollais L, Azzouzi R, et al.: Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother-brother dependence. Ann Hum Genet 67 (Pt 2): 125-37, 2003.
60. Pakkanen S, Baffoe-Bonnie AB, Matikainen MP, et al.: Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance. Hum Genet 121 (2): 257-67, 2007.

Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk

Various research methods have been used to understand the genetic variation that is associated with prostate cancer. Different methods can identify unique phenotypes or inheritance patterns. The sections below describe prostate cancer research, which uses various methods to uncover the genetic basis of prostate cancer. Linkage studies can help identify susceptibility genes that predispose to genetic disease. These studies are typically performed on large, high-risk families in which multiple cases of a particular disease have occurred. Typically, pathogenic variants identified through linkage analyses are rare in the population, are moderately to highly penetrant in families, and have large (e.g., relative risk [RR] >2.0) effect sizes. Pathogenic variants that are identified in linkage studies allow individuals to receive clinical treatment.

Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have low to modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

Linkage Analyses

Introduction to linkage analyses

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals within the extended family and looks for associations between inherited genetic markers and the disease trait. If an association between a variation at a particular chromosomal region and the disease trait is found (linkage), it provides statistical evidence that the genetic locus harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is influenced by the following:

• Family size and having a sufficient number of family members who volunteer to contribute DNA.
• The number of disease cases in each family.
• Factors related to age at diagnosis (e.g., utilization of screening).
• Gender differences in disease risk (not relevant in prostate cancer but remains relevant in linkage analysis for other conditions).
• Heterogeneity of disease in cases (e.g., aggressive vs. nonaggressive phenotype).
• Genetic heterogeneity (e.g., multiple genetic variants contribute to the same condition).
• The accuracy of family history information.

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

1. Three or more affected first-degree relatives (father, brother, son).
2. Affected relatives in three successive generations of either maternal or paternal lineages.
3. At least two relatives affected at age 55 years or younger.

Using these criteria, surgical series have reported that approximately 3% to 5% of men with prostate cancer will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a man's lifetime risk of prostate cancer is one in eight,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer, obscuring the genetic signal. There are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease, although current advances in the understanding of molecular phenotypes of prostate cancer may be informative in identifying inherited prostate cancer. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score ≥7, PSA ≥20 ng/mL) in an affected man.[5,6,7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Susceptibility loci identified in linkage analyses

Linkage analyses led to the successful identification of HOXB13 at 17q21-22 as a prostate cancer susceptibility gene.[12] Pathogenic variants in this gene are more commonly identified in multicase families and/or as evidence of early-onset disease, and these findings have been confirmed in multiple studies conducted throughout the world.

In 2012, the first prostate cancer–specific germline genetic variant was identified in a linkage study.[12] An initial linkage signal was found in the 17q21-22 region and was followed by targeted sequencing. This led to the identification of a rare (carrier frequency, 1.4%), recurrent variant (G84E; rs13821397) in the HOXB13 gene in four families with hereditary prostate cancer. A subsequent international study of more than 2,400 prostate cancer families found that 112 (4.6%) families of European descent had at least one HOXB13 pathogenic variant carrier. The carrier frequency was higher in affected men (47%) than it was in unaffected men (31%), with an odds ratio (OR) of 4.3 (95% confidence interval [CI], 2.3–8.0) for prostate cancer associated with the G84E pathogenic variant.[13] In 2013, a meta-analysis of 24 published studies (24,213 cases; 73,631 controls) estimated an overall RR of 4.1 (95% CI, 3.1–5.5) for the HOXB13 G84E variant. However, the frequency of this risk allele varied substantially across countries, with the highest prevalence in Nordic countries.[14] The clinical utility of testing for the G84E variant is yet to be determined.[15] For more information, see the HOXB13 section.

Linkage analyses in various familial phenotypes

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint heterogeneity logarithm of the odds (HLOD) scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[16,17] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide variant (SNV) platform.[18] Additional studies that include a larger number of African American families are needed to confirm these findings.

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analyses have been performed in families with clinically high-risk features such as: Gleason score 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One study of 123 families with two or more affected family members with aggressive prostate cancer discovered linkage at chromosome 22q11 and 22q12.3-q13.1.[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[19] Another linkage analysis utilizing a higher resolution marker set in 348 families with aggressive prostate cancer found 8q24 to be a region with strong evidence of linkage.[20] Additional regions of linkage with aggressive disease with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified. Several studies of hereditary prostate cancer families are under way on the basis of next-generation sequencing (i.e., whole-exome sequencing) and dense genotyping arrays. Results from these efforts may provide further insight on inherited susceptibility in high-risk families.

Evidence suggests that many of the prostate cancer risk loci discovered via linkage analysis account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity. Several proposed prostate cancer susceptibility loci have been identified in families with multiple prostate cancer–affected individuals. Genes residing at risk loci discovered using linkage analysis include HPC1/RNASEL (1q25), PCAP (1q42.2-43), HPCX (Xq27-28), CAPB (1p36), and HPC20 (20q13),[21] as well as intergenic regions at 8p and 8q.[17,22] In addition, the following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (≥2) logarithm of the odds (LOD) score, HLOD score, or summary LOD score: 3p14, 3p24-26, 5q11-12, 5q35, 6p22.3, 7q32, 8q13, 9q34, 11q22, 15q11, 16q23, 17q21-22, and 22q12.3.[1,9,21] Data on the proposed phenotype associated with each locus are often limited, and validation studies are needed to firmly establish associations.

Case-Control Studies of Candidate Genes and Pathways

A case-control study evaluates factors of interest to assess for association with a condition. The design involves cases with a condition of interest, such as a specific disease or genetic variant, and a control sample without that condition. In most cases, researchers seek to match cases and controls with as many characteristics as possible (e.g., age, gender, and ethnicity) in order to isolate a particular genetic variant as the sole focus of interrogation. Limitations of case-control design with regard to identifying genetic factors include the following:[23,24]

• Stratification of the populations being studied (i.e., known or unknown population-based differences between cases and controls that could result in false-positive associations).[25]
• Genetic heterogeneity (i.e., various alleles or loci beyond those under investigation can result in a similar phenotype).
• The high prevalence of the disease in the population, potentially affecting the purity of the control arm.
• Lack of appropriate statistical power to confidently declare an association.

Because of potential confounders in this line of inquiry, validation in independent datasets is required to establish a true association.[23,24]

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR gene is a logical gene to interrogate because it is expressed during all stages of prostate carcinogenesis and is routinely overexpressed in advanced disease.[26,27] Further, depletion of an AR signal reliably leads to prostate cancer regression. Germline variants at the AR locus have been extensively studied. For example, the length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene appear to vary in the population and early studies suggested a possible connection to prostate cancer risk.[26,28,29,30,31,32,33,34,35,36,37,38] However, no germline variant at the AR locus has been definitively associated with the disease.[39]

Molecular epidemiology studies have also examined genetic polymorphisms of the SRD5A2 gene, which is involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone by 5-alpha-reductase type II.[40] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[41,42] Several case-control studies have been performed, leading to well-powered meta-analyses, which have failed to demonstrate a clear association between variation of this gene and prostate cancer risk.[43,44,45,46,47]

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNVs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNV in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[48] Other ER-beta polymorphisms have been reported as associated with modest risk.[49,50,51]ER-alpha gene variants have also been investigated and some studies have suggested a possible connection with prostate cancer. Given the lack of a convincing statistical signal, any positive associations from these studies require replication in larger datasets.

Germline pathogenic variants in the tumor suppressor gene E-cadherin (CDH1) cause a hereditary form of gastric carcinoma. A SNV designated -160C/A, located in the promoter region of CDH1, has been found to alter the transcriptional activity of this gene.[52] Because somatic mutations in CDH1 have been implicated in the development of invasive malignancies in a number of different cancers,[53] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.11–1.60).[54] A subsequent meta-analysis confirmed a modest association with the CDH1 -160C/A polymorphism.[55] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

In a whole-exome germline sequencing cohort of 200 African American men and 452 European American men with aggressive prostate cancer along with ethnic- and age-matched controls, researchers found that variants in TET2 were associated with aggressive disease in the African American subpopulation. These variants were present in 24.4% of African American cases compared with 9.6% of controls.[56]

Several other gene groups have been the focus of case-control studies, including the steroid hormone pathway,[57,58] toll-like receptor genes,[59,60,61,62,63,64,65,66,67] the folate pathway,[68] p53,[69] and several others.[70,71,72,73,74,75,76,77,78]

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBN, CHEK2, AR, SRD5A2, ER-beta, CDH1, and the toll-like receptor genes. The clinical validity and utility of genetic testing for any of these genes to assess risk has not been established. Validation and prospective series are needed in order to prove clinical utility.

Admixture Mapping

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[79] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[80,81]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African American individuals. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

• 5q35 (Z-score, 3.1) [82]
• 7q31 (Z-score, 4.6) [82]
• 8q24 (LOD score, 7.1) [82,83]

Recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[84] As a result, fewer genetic markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer. This method requires less genetic markers than a successful GWAS.[80] For more information, see the GWAS section.

Genome-wide Association Studies

Overview

• GWAS can identify inherited genetic variants that influence a specific phenotype, such as risk of a particular disease.
• For complex diseases, such as prostate cancer, risk of developing the disease is the product of multiple genetic and environmental factors; each individual factor contributes relatively little to overall risk.
• To date, GWAS have discovered more than 150 common genetic variants associated with prostate cancer risk.
• Individuals can be genotyped for all known prostate cancer risk markers relatively easily; but, to date, studies have not demonstrated that this information substantially refines risk estimates from commonly used variables, such as family history.
• The clinical relevance of variants identified from GWAS remains unclear.

Introduction to GWAS

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[85] including prostate cancer.[86] This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[87,88] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to "scan" the genome without having to test all tens of millions of known SNVs. GWAS can test approximately 1 million to 5 million SNVs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNV between cases and controls. Promising signals–in which allele frequencies deviate significantly in cases when compared with control populations–are validated in replication datasets. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNVs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently when standard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 × 10^-7.[89,90,91]

To date, more than 150 variants associated with prostate cancer have been identified by well-powered GWAS. These variants have been validated in independent cohorts (for more information, see National Human Genome Research Institute GWAS catalog).[92,93,94,95] These studies have identified convincing associations between specific inherited variants and prostate cancer risk. In addition, men with early-onset prostate cancer have a higher cumulative number of risk alleles when compared with older prostate cancer cases and public controls.[96] However, the findings should be qualified with a few important considerations:

1. GWAS reported thus far have been designed to identify genetic polymorphisms that are relatively common in the population. It is very unlikely that an allele with high frequency in the population by itself contributes substantially to cancer risk. This, coupled with the polygenic nature of prostate tumorigenesis, means that the contribution by any single variant identified by GWAS to date is quite small, generally with an OR for disease risk of less than 1.3. In addition, despite extensive genome-wide interrogation of common polymorphisms in tens of thousands of cases and controls, GWAS findings to date do not account for even half of the genetic component of prostate cancer risk.[92,97,98,99]
2. Variants uncovered by GWAS are not likely to be the ones directly contributing to disease risk. As mentioned above, SNVs exist in linkage disequilibrium blocks and are merely proxies for a set of variants—both known and previously undiscovered—within a given block. The causal allele is located somewhere within that linkage disequilibrium block.
3. Admixture by groups of different ancestry can confound GWAS findings (i.e., a statistically significant finding could reflect a disproportionate number of subjects in the cases versus controls, rather than a true association with disease). Therefore, GWAS subjects, by design, comprise only one ancestral group. As a result, some populations remain underrepresented in genome-wide analyses.

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[100]

Susceptibility loci identified in GWAS

Beginning in 2006, multiple genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24.[101,102,103,104,105,106,107,108,109,110,111,112,113,114] Since that time, more than ten genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions. The population-attributable risk of prostate cancer from the 8q24 risk alleles reported to date is 9.4%.[115]

Since prostate cancer risk loci have been discovered at 8q24, more than 250 variants have been identified at other chromosomal risk loci. These chromosomal risk loci were detected by multistage GWAS, which were comprised of thousands of cases and controls and were validated in independent cohorts.[116] The most convincing associations reported to date for men of European ancestry are annotated in the National Human Genome Research Institute GWAS catalog.

GWAS in populations of non-European ancestry

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNV frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[117] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are annotated in the National Human Genome Research Institute GWAS catalog.

The African American population is of particular interest because American men with West African ancestry are at higher risk of prostate cancer than any other group. A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[118] Another study examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls.[119] The majority of risk alleles (approximately 83%) are shared across African American and European American populations. A GWAS meta-analysis of 10,202 cases and 10,810 controls of African ancestry found novel signals on chromosomes 13q24 and 22q12, which were uniquely associated with risk in this high-risk population.[94] A study of 4,853 cases and 4,678 controls of African ancestry identified three independent associations that were subsequently replicated. All three variants were within or near long noncoding RNAs (lncRNAs) previously associated with prostate cancer, and two of the variants were unique to men of African ancestry.[120]

Statistically well-powered GWAS have also been launched to examine inherited cancer risk in Japanese and Chinese populations. Investigators discovered that these populations share many risk regions observed in African American men.[121,122,123,124] Additionally, risk regions that are unique to these ancestral groups were identified (for more information, see the National Human Genome Research Institute GWAS catalog). Ongoing work in larger cohorts will validate and expand upon these findings.

Clinical study of GWAS findings

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. As increasing numbers of risk SNVs have been discovered, they have been applied to clinical cohorts alongside traditional variables such as PSA and family history, although the clinical utility of this information has not been established.

An initial study of the first five known risk SNVs could not demonstrate that they added clinically meaningful data.[125] In later trials, larger risk-SNV panels also could not demonstrate usefulness for a large proportion of the screening population. However, the small subset of men carrying large numbers of risk alleles, especially those with positive family histories, were at appreciably high risk of developing prostate cancer.[125,126]

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[127] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNVs have "poor discriminative ability" to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional common risk alleles (alleles carried by >1%–5% of individuals within the population).[128]

Polygenic risk scores

In a 2018 study, 147 GWAS variants known to be associated with prostate cancer were used to calculate a polygenic risk score (PRS) for more than 140,000 men.[95] In 2021, this scoring system, which accounts for genetic dose (i.e., homozygosity vs. heterozygosity) and strength of prostate cancer risk association, was applied to a multi-ethnic cohort of over 100,000 prostate cancer cases and 100,000 controls. This scoring system used 269 known risk variants. In this study, the PRS was called a genetic risk score (GRS). When focusing on men in the top decile of GRSs and comparing them to men in the middle of the distribution, men with European ancestry had an OR of 5.06 (95% CI, 4.84–5.29), and men with African ancestry had an OR of 3.74 (95% CI, 3.36–4.17). When comparing across ethnic groups (with individuals of European, African, East Asian, and Hispanic ancestries) and across all deciles, men with African ancestry were at the highest risk of developing prostate cancer, with a mean GRS that was 2.18-times higher than that of men with European ancestry. Men with East Asian ancestry had a mean GRS that was 0.73-times lower than that of men with European ancestry.[116]

The prostate cancer PRS's predictive value was maintained when it was applied to populations of men who carry deleterious variants in BRCA1 or BRCA2; this was particularly true among those in the top 95% distribution of the PRS.[129,130] However, initial studies suggested that these associations were modest when compared with those in the general population. This is likely because BRCA1 and BRCA2 carriers have a substantially increased risk of developing prostate cancer than individuals in the general population.

The Stockholm-3 Model (S3M) was developed on the basis of a study of 58,000 Swedish men aged 50 to 69 years. Men were genotyped for 233 prostate cancer risk–associated variants, and these data were used with other clinical data to risk-stratify men. Compared with PSA alone (area under the curve [AUC], 0.56), the addition of SNVs to clinical factors (S3M) improved prediction (AUC, 0.75) of clinically significant (i.e., Gleason score ≥7) prostate cancer.[131] Another community-based study (BARCODE1) of 5,000 men aged 55 to 69 years in the United Kingdom involves genotyping for 167 risk SNVs, with men in the top 10% of the PRS undergoing prostate biopsies. This study should provide additional information on the potential clinical utility of the PRS for guiding prostate cancer screening protocols.[86] PRSs have been shown to be additive to risk attributed to rare pathogenic alleles, including BRCA1/BRCA2[129] and HOXB13.[132]

In 2021, a prospective study was done on participants from the U.K. Biobank. This cohort consisted of 208,685 men (mostly of European ancestry). Results suggested that prostate cancer risk–associated single nucleotide polymorphisms (SNPs) can provide useful information when they are added to an individual's family history and rare pathogenic variant status.[133] SNP carriers in the high-risk quartile had an increased risk to develop prostate cancer (RR, 1.97; 95% CI, 1.87–2.07). Men in the high-risk quartile also had an increased C-statistic for differentiating prostate cancer incidence when prostate cancer risk–associated SNP burden was added to family history and rare pathogenic variant status (C-statistic for family history, 0.58; C-statistic for pathogenic variant status, 0.67). However, the long-term clinical outcome monitoring was short, particularly for prostate cancer–specific mortality. It is unclear if screening PRSs can appreciably influence long-term outcomes.

Current GWAS findings account for only a portion of the estimated 58% of disease risk that is heritable. In addition, around 6% of the familial RR of prostate cancer has been attributed to rare genetic variants.[86] Ongoing research attempts to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with ORs that are associated with higher prostate cancer risk.[134] Research focused on the associated risk of prostate cancer and the predictability of PRSs is ongoing.[135] To date, over 250 prostate cancer risk variants have been discovered via GWAS.[116] In an independent cohort of over 13,000 men, a panel of 261 GWAS-derived risk variants significantly predicted disease risk.[136] Disease risk was best predicted at the highest and lowest deciles, where the highest decile represented the largest risk variant burden, and the lowest decile represented the smallest risk variant burden. In the top decile, the OR for prostate cancer diagnosis was 3.81 (95% CI, 1.48–10.19) in men of African ancestry and 3.89 (95% CI, 3.24– 4.68) in men of European ancestry when compared with men who were at an average risk of developing prostate cancer. In the lowest decile, the ORs were 0.15 (95% CI, 0.01–0.92) and 0.34 (95% CI, 0.25–0.46) in men of African ancestry and men of European ancestry, respectively.[136]

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful. Finally, GWAS are providing more insight into the mechanism of prostate cancer risk. Notably, almost all reported prostate cancer risk alleles reside in nonprotein-coding regions of the genome; however, the underlying biological mechanism of disease susceptibility was initially unclear. It is now apparent that a large proportion of risk variants affect the activity of regulatory elements and, in turn, distal genes.[137,138,139,140,140,141,142,143,144,145] As GWAS elucidate these networks, it is hoped that new therapies and chemopreventive strategies will follow.

Conclusions

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. However, when combined into a PRS, these confirmed genetic risk variants may prove to be useful for prostate cancer risk stratification and to identify men for targeted screening and early detection. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[146] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Inherited Single Nucleotide Variants (SNVs) Associated With Prostate Cancer Aggressiveness

Prostate cancer is biologically and clinically heterogeneous. Many tumors are indolent and are successfully managed with observation alone. Other tumors are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed because sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers because they are present, easily detectable, and static throughout life.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. As described below, germline SNVs associated with prostate cancer aggressiveness are derived primarily from three methods of analysis: 1) annotation of common variants within candidate risk genes; 2) assessment of known overall prostate cancer risk SNVs for aggressiveness; and 3) GWAS for prostate cancer aggressiveness. Further work is needed to validate findings and assess these associations prospectively.

Like studies of the genetics of overall prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes.[147,148,149,150,151,152,153] Next, as GWAS revealed prostate cancer risk SNVs, several research teams sought to determine whether certain overall risk SNVs were also associated with aggressiveness.[154,155,156,157,158,159,160,161]

There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer.

Associations between inherited variants and prostate cancer aggressiveness have been reported. A multistage, case-only GWAS led by the National Cancer Institute examined 12,518 prostate cancer cases and discovered an association between genotype and Gleason score at two polymorphisms: rs35148638 at 5q14.3 (RASA1, P = 6.49 × 10^-9) and rs78943174 at 3q26.31 (NAALADL2, P = 4.18 × 10^-8).[162] The study also found a significant association for a SNV at 19q13, which was previously reported to be the location of a genetic variant associated with aggressive disease. More recently, that SNV (rs11672691) at the 19q13 locus was associated with elevated transcript levels of PCAT19 and CEACAM21, genes implicated in prostate cancer growth and tumor progression.[163,164] Although the associations discovered in these studies may provide valuable insight into the biology of high-grade disease, it is unclear whether they will prove clinically useful. This study raises the issue of the definition of "prostate cancer aggressiveness." Gleason score is used as a prognostic marker but is not a perfect surrogate for prostate cancer–specific survival or overall survival.

A few GWAS designed specifically to focus on prostate cancer subjects with documented disease-related outcomes have been launched. In one study—a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths)—no SNV was significantly associated with prostate cancer–specific survival.[165] Similarly, in a smaller study assessing prostate cancer–specific mortality (196 lethal cases, 368 long-term survivors), no variants were significantly associated with outcome.[166] More recently, a GWAS was conducted across 24,023 prostate cancer patients and similarly found no significant association between genetic variants and prostate cancer survival.[162] The authors of these studies concluded that any SNV associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%).

A GWAS of Swedish men diagnosed with prostate cancer found a genetic variant at the AOX1 locus, which was significantly associated with survival.[167] Another study involving a cohort of 12,082 patients with prostate cancer confirmed associations of genetic variants in IL4, MGMT, and AKT1 with prostate cancer–specific mortality.[168] Although an initial GWAS analysis of 24,023 patients with prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) and Breast and Prostate Cancer Cohort Consortium (BPC3) study groups did not find any SNVs that were significantly associated with survival,[165] an updated analysis of those cohorts is under way.

References:

1. Easton DF, Schaid DJ, Whittemore AS, et al.: Where are the prostate cancer genes?--A summary of eight genome wide searches. Prostate 57 (4): 261-9, 2003.
2. Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.
3. Siddiqui SA, Sengupta S, Slezak JM, et al.: Impact of familial and hereditary prostate cancer on cancer specific survival after radical retropubic prostatectomy. J Urol 176 (3): 1118-21, 2006.
4. American Cancer Society: Cancer Facts and Figures 2022. American Cancer Society, 2022. Available online. Last accessed October 7, 2022.
5. Stanford JL, McDonnell SK, Friedrichsen DM, et al.: Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness. Prostate 66 (3): 317-25, 2006.
6. Chang BL, Isaacs SD, Wiley KE, et al.: Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease. Prostate 64 (4): 356-61, 2005.
7. Lange EM, Ho LA, Beebe-Dimmer JL, et al.: Genome-wide linkage scan for prostate cancer susceptibility genes in men with aggressive disease: significant evidence for linkage at chromosome 15q12. Hum Genet 119 (4): 400-7, 2006.
8. Witte JS, Goddard KA, Conti DV, et al.: Genomewide scan for prostate cancer-aggressiveness loci. Am J Hum Genet 67 (1): 92-9, 2000.
9. Witte JS, Suarez BK, Thiel B, et al.: Genome-wide scan of brothers: replication and fine mapping of prostate cancer susceptibility and aggressiveness loci. Prostate 57 (4): 298-308, 2003.
10. Slager SL, Zarfas KE, Brown WM, et al.: Genome-wide linkage scan for prostate cancer aggressiveness loci using families from the University of Michigan Prostate Cancer Genetics Project. Prostate 66 (2): 173-9, 2006.
11. Slager SL, Schaid DJ, Cunningham JM, et al.: Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q. Am J Hum Genet 72 (3): 759-62, 2003.
12. Ewing CM, Ray AM, Lange EM, et al.: Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 366 (2): 141-9, 2012.
13. Xu J, Lange EM, Lu L, et al.: HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet 132 (1): 5-14, 2013.
14. Shang Z, Zhu S, Zhang H, et al.: Germline homeobox B13 (HOXB13) G84E mutation and prostate cancer risk in European descendants: a meta-analysis of 24,213 cases and 73, 631 controls. Eur Urol 64 (1): 173-6, 2013.
15. Schroeck FR, Zuhlke KA, Siddiqui J, et al.: Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy. J Urol 189 (3): 849-53, 2013.
16. Baffoe-Bonnie AB, Kittles RA, Gillanders E, et al.: Genome-wide linkage of 77 families from the African American Hereditary Prostate Cancer study (AAHPC). Prostate 67 (1): 22-31, 2007.
17. Xu J, Dimitrov L, Chang BL, et al.: A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet 77 (2): 219-29, 2005.
18. Ledet EM, Sartor O, Rayford W, et al.: Suggestive evidence of linkage identified at chromosomes 12q24 and 2p16 in African American prostate cancer families from Louisiana. Prostate 72 (9): 938-47, 2012.
19. Camp NJ, Farnham JM, Cannon-Albright LA: Localization of a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 in Utah high-risk pedigrees. Cancer Res 66 (20): 10205-12, 2006.
20. Lu L, Cancel-Tassin G, Valeri A, et al.: Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG. Prostate 72 (4): 410-26, 2012.
21. Lynch HT, Kosoko-Lasaki O, Leslie SW, et al.: Screening for familial and hereditary prostate cancer. Int J Cancer 138 (11): 2579-91, 2016.
22. Maier C, Herkommer K, Hoegel J, et al.: A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. Eur J Hum Genet 13 (3): 352-60, 2005.
23. Schork NJ, Fallin D, Thiel B, et al.: The future of genetic case-control studies. Adv Genet 42: 191-212, 2001.
24. Tang H, Quertermous T, Rodriguez B, et al.: Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 76 (2): 268-75, 2005.
25. Thomas DC, Witte JS: Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev 11 (6): 505-12, 2002.
26. Ruijter E, van de Kaa C, Miller G, et al.: Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 20 (1): 22-45, 1999.
27. Fromont G, Yacoub M, Valeri A, et al.: Differential expression of genes related to androgen and estrogen metabolism in hereditary versus sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 17 (6): 1505-9, 2008.
28. Ekman P: Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol 35 (5-6): 362-9, 1999.
29. Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22 (15): 3181-6, 1994.
30. Giovannucci E, Stampfer MJ, Krithivas K, et al.: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 94 (7): 3320-3, 1997.
31. Stanford JL, Just JJ, Gibbs M, et al.: Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 57 (6): 1194-8, 1997.
32. Platz EA, Giovannucci E, Dahl DM, et al.: The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 7 (5): 379-84, 1998.
33. Bratt O, Borg A, Kristoffersson U, et al.: CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. Br J Cancer 81 (4): 672-6, 1999.
34. Ekman P, Grönberg H, Matsuyama H, et al.: Links between genetic and environmental factors and prostate cancer risk. Prostate 39 (4): 262-8, 1999.
35. Lange EM, Chen H, Brierley K, et al.: The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiol Biomarkers Prev 9 (4): 439-42, 2000.
36. Edwards SM, Badzioch MD, Minter R, et al.: Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int J Cancer 84 (5): 458-65, 1999.
37. Correa-Cerro L, Wöhr G, Häussler J, et al.: (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. Eur J Hum Genet 7 (3): 357-62, 1999.
38. Mononen N, Ikonen T, Autio V, et al.: Androgen receptor CAG polymorphism and prostate cancer risk. Hum Genet 111 (2): 166-71, 2002.
39. Freedman ML, Pearce CL, Penney KL, et al.: Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. Am J Hum Genet 76 (1): 82-90, 2005.
40. Reichardt JK, Makridakis N, Henderson BE, et al.: Genetic variability of the human SRD5A2 gene: implications for prostate cancer risk. Cancer Res 55 (18): 3973-5, 1995.
41. Brawley OW, Ford LG, Thompson I, et al.: 5-Alpha-reductase inhibition and prostate cancer prevention. Cancer Epidemiol Biomarkers Prev 3 (2): 177-82, 1994.
42. Ross RK, Bernstein L, Lobo RA, et al.: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339 (8798): 887-9, 1992.
43. Ntais C, Polycarpou A, Ioannidis JP: SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12 (7): 618-24, 2003.
44. Wang C, Tao W, Chen Q, et al.: SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis. Prostate 70 (2): 170-8, 2010.
45. Li J, Coates RJ, Gwinn M, et al.: Steroid 5-{alpha}-reductase Type 2 (SRD5a2) gene polymorphisms and risk of prostate cancer: a HuGE review. Am J Epidemiol 171 (1): 1-13, 2010.
46. Li Q, Zhu Y, He J, et al.: Steroid 5-alpha-reductase type 2 (SRD5A2) V89L and A49T polymorphisms and sporadic prostate cancer risk: a meta-analysis. Mol Biol Rep 40 (5): 3597-608, 2013.
47. Li X, Huang Y, Fu X, et al.: Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer. Mutagenesis 26 (3): 371-83, 2011.
48. Thellenberg-Karlsson C, Lindström S, Malmer B, et al.: Estrogen receptor beta polymorphism is associated with prostate cancer risk. Clin Cancer Res 12 (6): 1936-41, 2006.
49. Dai ZJ, Wang BF, Ma YF, et al.: Current evidence on the relationship between rs1256049 polymorphism in estrogen receptor-β gene and cancer risk. Int J Clin Exp Med 7 (12): 5031-40, 2014.
50. Holt SK, Kwon EM, Fu R, et al.: Association of variants in estrogen-related pathway genes with prostate cancer risk. Prostate 73 (1): 1-10, 2013.
51. Safarinejad MR, Safarinejad S, Shafiei N, et al.: Estrogen receptors alpha (rs2234693 and rs9340799), and beta (rs4986938 and rs1256049) genes polymorphism in prostate cancer: evidence for association with risk and histopathological tumor characteristics in Iranian men. Mol Carcinog 51 (Suppl 1): E104-17, 2012.
52. Li LC, Chui RM, Sasaki M, et al.: A single nucleotide polymorphism in the E-cadherin gene promoter alters transcriptional activities. Cancer Res 60 (4): 873-6, 2000.
53. Wang GY, Lu CQ, Zhang RM, et al.: The E-cadherin gene polymorphism 160C->A and cancer risk: A HuGE review and meta-analysis of 26 case-control studies. Am J Epidemiol 167 (1): 7-14, 2008.
54. Wang L, Wang G, Lu C, et al.: Contribution of the -160C/A polymorphism in the E-cadherin promoter to cancer risk: a meta-analysis of 47 case-control studies. PLoS One 7 (7): e40219, 2012.
55. Chang Z, Zhou H, Liu Y: Promoter methylation and polymorphism of E-cadherin gene may confer a risk to prostate cancer: a meta-analysis based on 22 studies. Tumour Biol 35 (10): 10503-13, 2014.
56. Koboldt DC, Kanchi KL, Gui B, et al.: Rare Variation in TET2 Is Associated with Clinically Relevant Prostate Carcinoma in African Americans. Cancer Epidemiol Biomarkers Prev 25 (11): 1456-1463, 2016.
57. Cunningham JM, Hebbring SJ, McDonnell SK, et al.: Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. Cancer Epidemiol Biomarkers Prev 16 (5): 969-78, 2007.
58. Beuten J, Gelfond JA, Franke JL, et al.: Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 18 (6): 1869-80, 2009.
59. De Marzo AM, Platz EA, Sutcliffe S, et al.: Inflammation in prostate carcinogenesis. Nat Rev Cancer 7 (4): 256-69, 2007.
60. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 4 (7): 499-511, 2004.
61. Zheng SL, Augustsson-Bälter K, Chang B, et al.: Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res 64 (8): 2918-22, 2004.
62. Chen YC, Giovannucci E, Lazarus R, et al.: Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res 65 (24): 11771-8, 2005.
63. Cheng I, Plummer SJ, Casey G, et al.: Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (2): 352-5, 2007.
64. Sun J, Wiklund F, Zheng SL, et al.: Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J Natl Cancer Inst 97 (7): 525-32, 2005.
65. Chen YC, Giovannucci E, Kraft P, et al.: Association between Toll-like receptor gene cluster (TLR6, TLR1, and TLR10) and prostate cancer. Cancer Epidemiol Biomarkers Prev 16 (10): 1982-9, 2007.
66. Weng PH, Huang YL, Page JH, et al.: Polymorphisms of an innate immune gene, toll-like receptor 4, and aggressive prostate cancer risk: a systematic review and meta-analysis. PLoS One 9 (10): e110569, 2014.
67. Jing JJ, Li M, Yuan Y: Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in cancer: a meta-analysis. Gene 499 (2): 237-42, 2012.
68. Collin SM, Metcalfe C, Zuccolo L, et al.: Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 18 (9): 2528-39, 2009.
69. Lu Y, Liu Y, Zeng J, et al.: Association of p53 codon 72 polymorphism with prostate cancer: an update meta-analysis. Tumour Biol 35 (5): 3997-4005, 2014.
70. Zheng SL, Chang BL, Faith DA, et al.: Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk. Cancer Res 62 (22): 6485-8, 2002.
71. Daugherty SE, Shugart YY, Platz EA, et al.: Polymorphic variants in alpha-methylacyl-CoA racemase and prostate cancer. Prostate 67 (14): 1487-97, 2007.
72. Levin AM, Zuhlke KA, Ray AM, et al.: Sequence variation in alpha-methylacyl-CoA racemase and risk of early-onset and familial prostate cancer. Prostate 67 (14): 1507-13, 2007.
73. Dong X, Wang L, Taniguchi K, et al.: Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 72 (2): 270-80, 2003.
74. Cybulski C, Wokołorczyk D, Kluźniak W, et al.: An inherited NBN mutation is associated with poor prognosis prostate cancer. Br J Cancer 108 (2): 461-8, 2013.
75. Nurminen R, Wahlfors T, Tammela TL, et al.: Identification of an aggressive prostate cancer predisposing variant at 11q13. Int J Cancer 129 (3): 599-606, 2011.
76. Nurminen R, Lehtonen R, Auvinen A, et al.: Fine mapping of 11q13.5 identifies regions associated with prostate cancer and prostate cancer death. Eur J Cancer 49 (15): 3335-43, 2013.
77. Narla G, Difeo A, Reeves HL, et al.: A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 65 (4): 1213-22, 2005.
78. Hebbring SJ, Fredriksson H, White KA, et al.: Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (5): 935-8, 2006.
79. Mao X, Bigham AW, Mei R, et al.: A genomewide admixture mapping panel for Hispanic/Latino populations. Am J Hum Genet 80 (6): 1171-8, 2007.
80. McKeigue PM: Prospects for admixture mapping of complex traits. Am J Hum Genet 76 (1): 1-7, 2005.
81. McKeigue PM: Mapping genes that underlie ethnic differences in disease risk: methods for detecting linkage in admixed populations, by conditioning on parental admixture. Am J Hum Genet 63 (1): 241-51, 1998.
82. Bock CH, Schwartz AG, Ruterbusch JJ, et al.: Results from a prostate cancer admixture mapping study in African-American men. Hum Genet 126 (5): 637-42, 2009.
83. Freedman ML, Haiman CA, Patterson N, et al.: Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A 103 (38): 14068-73, 2006.
84. Race, Ethnicity, and Genetics Working Group: The use of racial, ethnic, and ancestral categories in human genetics research. Am J Hum Genet 77 (4): 519-32, 2005.
85. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007.
86. Benafif S, Kote-Jarai Z, Eeles RA, et al.: A Review of Prostate Cancer Genome-Wide Association Studies (GWAS). Cancer Epidemiol Biomarkers Prev 27 (8): 845-857, 2018.
87. The International HapMap Consortium: The International HapMap Project. Nature 426 (6968): 789-96, 2003.
88. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.
89. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006.
90. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006.
91. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007.
92. Al Olama AA, Kote-Jarai Z, Berndt SI, et al.: A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 46 (10): 1103-9, 2014.
93. Eeles R, Goh C, Castro E, et al.: The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol 11 (1): 18-31, 2014.
94. Conti DV, Wang K, Sheng X, et al.: Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. J Natl Cancer Inst 109 (8): , 2017.
95. Schumacher FR, Al Olama AA, Berndt SI, et al.: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat Genet 50 (7): 928-936, 2018.
96. Lange EM, Salinas CA, Zuhlke KA, et al.: Early onset prostate cancer has a significant genetic component. Prostate 72 (2): 147-56, 2012.
97. Kote-Jarai Z, Olama AA, Giles GG, et al.: Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet 43 (8): 785-91, 2011.
98. Eeles RA, Olama AA, Benlloch S, et al.: Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet 45 (4): 385-91, 391e1-2, 2013.
99. Dadaev T, Saunders EJ, Newcombe PJ, et al.: Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. Nat Commun 9 (1): 2256, 2018.
100. Jorgenson E, Witte JS: Genome-wide association studies of cancer. Future Oncol 3 (4): 419-27, 2007.
101. Amundadottir LT, Sulem P, Gudmundsson J, et al.: A common variant associated with prostate cancer in European and African populations. Nat Genet 38 (6): 652-8, 2006.
102. Schumacher FR, Feigelson HS, Cox DG, et al.: A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res 67 (7): 2951-6, 2007.
103. Suuriniemi M, Agalliu I, Schaid DJ, et al.: Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol Biomarkers Prev 16 (4): 809-14, 2007.
104. Wang L, McDonnell SK, Slusser JP, et al.: Two common chromosome 8q24 variants are associated with increased risk for prostate cancer. Cancer Res 67 (7): 2944-50, 2007.
105. Yeager M, Orr N, Hayes RB, et al.: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39 (5): 645-9, 2007.
106. Zheng SL, Sun J, Cheng Y, et al.: Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst 99 (20): 1525-33, 2007.
107. Savage SA, Greene MH: The evidence for prostate cancer risk loci at 8q24 grows stronger. J Natl Cancer Inst 99 (20): 1499-501, 2007.
108. Salinas CA, Kwon E, Carlson CS, et al.: Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 17 (5): 1203-13, 2008.
109. Zheng SL, Hsing AW, Sun J, et al.: Association of 17 prostate cancer susceptibility loci with prostate cancer risk in Chinese men. Prostate 70 (4): 425-32, 2010.
110. Zeegers MP, Khan HS, Schouten LJ, et al.: Genetic marker polymorphisms on chromosome 8q24 and prostate cancer in the Dutch population: DG8S737 may not be the causative variant. Eur J Hum Genet 19 (1): 118-20, 2011.
111. Gudmundsson J, Sulem P, Manolescu A, et al.: Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39 (5): 631-7, 2007.
112. Haiman CA, Patterson N, Freedman ML, et al.: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39 (5): 638-44, 2007.
113. Yeager M, Chatterjee N, Ciampa J, et al.: Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat Genet 41 (10): 1055-7, 2009.
114. Al Olama AA, Kote-Jarai Z, Giles GG, et al.: Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet 41 (10): 1058-60, 2009.
115. Matejcic M, Saunders EJ, Dadaev T, et al.: Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nat Commun 9 (1): 4616, 2018.
116. Conti DV, Darst BF, Moss LC, et al.: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat Genet 53 (1): 65-75, 2021.
117. Cook MB, Wang Z, Yeboah ED, et al.: A genome-wide association study of prostate cancer in West African men. Hum Genet 133 (5): 509-21, 2014.
118. Haiman CA, Chen GK, Blot WJ, et al.: Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet 7 (5): e1001387, 2011.
119. Han Y, Signorello LB, Strom SS, et al.: Generalizability of established prostate cancer risk variants in men of African ancestry. Int J Cancer 136 (5): 1210-7, 2015.
120. Han Y, Rand KA, Hazelett DJ, et al.: Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 108 (7): , 2016.
121. Takata R, Akamatsu S, Kubo M, et al.: Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat Genet 42 (9): 751-4, 2010.
122. Akamatsu S, Takata R, Haiman CA, et al.: Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese. Nat Genet 44 (4): 426-9, S1, 2012.
123. Xu J, Mo Z, Ye D, et al.: Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4. Nat Genet 44 (11): 1231-5, 2012.
124. Takata R, Takahashi A, Fujita M, et al.: 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population. Nat Commun 10 (1): 4422, 2019.
125. Zheng SL, Sun J, Wiklund F, et al.: Cumulative association of five genetic variants with prostate cancer. N Engl J Med 358 (9): 910-9, 2008.
126. Xu J, Sun J, Kader AK, et al.: Estimation of absolute risk for prostate cancer using genetic markers and family history. Prostate 69 (14): 1565-72, 2009.
127. Little J, Wilson B, Carter R, et al.: Multigene Panels in Prostate Cancer Risk Assessment. Agency for Healthcare Research and Quality (US), 2012. Evidence Report/Technology Assessment Number 209. Also available online. Last accessed November 22, 2022.
128. Park JH, Gail MH, Greene MH, et al.: Potential usefulness of single nucleotide polymorphisms to identify persons at high cancer risk: an evaluation of seven common cancers. J Clin Oncol 30 (17): 2157-62, 2012.
129. Lecarpentier J, Silvestri V, Kuchenbaecker KB, et al.: Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores. J Clin Oncol 35 (20): 2240-2250, 2017.
130. Barnes DR, Silvestri V, Leslie G, et al.: Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores. J Natl Cancer Inst 114 (1): 109-122, 2022.
131. Ström P, Nordström T, Aly M, et al.: The Stockholm-3 Model for Prostate Cancer Detection: Algorithm Update, Biomarker Contribution, and Reflex Test Potential. Eur Urol 74 (2): 204-210, 2018.
132. Karlsson R, Aly M, Clements M, et al.: A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk. Eur Urol 65 (1): 169-76, 2014.
133. Shi Z, Platz EA, Wei J, et al.: Performance of Three Inherited Risk Measures for Predicting Prostate Cancer Incidence and Mortality: A Population-based Prospective Analysis. Eur Urol 79 (3): 419-426, 2021.
134. Gudmundsson J, Sulem P, Gudbjartsson DF, et al.: A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44 (12): 1326-9, 2012.
135. Li-Sheng Chen S, Ching-Yuan Fann J, Sipeky C, et al.: Risk Prediction of Prostate Cancer with Single Nucleotide Polymorphisms and Prostate Specific Antigen. J Urol 201 (3): 486-495, 2019.
136. Plym A, Penney KL, Kalia S, et al.: Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer. J Natl Cancer Inst 114 (5): 771-774, 2022.
137. Freedman ML, Monteiro AN, Gayther SA, et al.: Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 43 (6): 513-8, 2011.
138. Pomerantz MM, Beckwith CA, Regan MM, et al.: Evaluation of the 8q24 prostate cancer risk locus and MYC expression. Cancer Res 69 (13): 5568-74, 2009.
139. Jia L, Landan G, Pomerantz M, et al.: Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 5 (8): e1000597, 2009.
140. Ahmadiyeh N, Pomerantz MM, Grisanzio C, et al.: 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 107 (21): 9742-6, 2010.
141. Sotelo J, Esposito D, Duhagon MA, et al.: Long-range enhancers on 8q24 regulate c-Myc. Proc Natl Acad Sci U S A 107 (7): 3001-5, 2010.
142. Meyer KB, Maia AT, O'Reilly M, et al.: A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression. PLoS Genet 7 (7): e1002165, 2011.
143. Spisák S, Lawrenson K, Fu Y, et al.: CAUSEL: an epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants. Nat Med 21 (11): 1357-63, 2015.
144. Hazelett DJ, Rhie SK, Gaddis M, et al.: Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS Genet 10 (1): e1004102, 2014.
145. Jiang J, Cui W, Vongsangnak W, et al.: Post genome-wide association studies functional characterization of prostate cancer risk loci. BMC Genomics 14 (Suppl 8): S9, 2013.
146. 1000 Genomes Project Consortium: A map of human genome variation from population-scale sequencing. Nature 467 (7319): 1061-73, 2010.
147. Sun T, Mary LG, Oh WK, et al.: Inherited variants in the chemokine CCL2 gene and prostate cancer aggressiveness in a Caucasian cohort. Clin Cancer Res 17 (6): 1546-52, 2011.
148. Sun T, Lee GS, Oh WK, et al.: Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a Caucasian population. Clin Cancer Res 16 (21): 5244-51, 2010.
149. Zabaleta J, Su LJ, Lin HY, et al.: Cytokine genetic polymorphisms and prostate cancer aggressiveness. Carcinogenesis 30 (8): 1358-62, 2009.
150. Ross PL, Cheng I, Liu X, et al.: Carboxypeptidase 4 gene variants and early-onset intermediate-to-high risk prostate cancer. BMC Cancer 9: 69, 2009.
151. Henríquez-Hernández LA, Valenciano A, Foro-Arnalot P, et al.: Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression. BMC Med Genet 15: 143, 2014.
152. Lin DW, FitzGerald LM, Fu R, et al.: Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality. Cancer Epidemiol Biomarkers Prev 20 (9): 1928-36, 2011.
153. Langeberg WJ, Kwon EM, Koopmeiners JS, et al.: Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes. Cancer Epidemiol Biomarkers Prev 19 (1): 258-64, 2010.
154. Pomerantz MM, Werner L, Xie W, et al.: Association of prostate cancer risk Loci with disease aggressiveness and prostate cancer-specific mortality. Cancer Prev Res (Phila) 4 (5): 719-28, 2011.
155. Bensen JT, Xu Z, Smith GJ, et al.: Genetic polymorphism and prostate cancer aggressiveness: a case-only study of 1,536 GWAS and candidate SNPs in African-Americans and European-Americans. Prostate 73 (1): 11-22, 2013.
156. He Y, Gu J, Strom S, et al.: The prostate cancer susceptibility variant rs2735839 near KLK3 gene is associated with aggressive prostate cancer and can stratify gleason score 7 patients. Clin Cancer Res 20 (19): 5133-9, 2014.
157. Helfand BT, Roehl KA, Cooper PR, et al.: Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases. Hum Genet 134 (4): 439-50, 2015.
158. Xu J, Isaacs SD, Sun J, et al.: Association of prostate cancer risk variants with clinicopathologic characteristics of the disease. Clin Cancer Res 14 (18): 5819-24, 2008.
159. Gallagher DJ, Vijai J, Cronin AM, et al.: Susceptibility loci associated with prostate cancer progression and mortality. Clin Cancer Res 16 (10): 2819-32, 2010.
160. Kader AK, Sun J, Isaacs SD, et al.: Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients. Prostate 69 (11): 1195-205, 2009.
161. Fitzgerald LM, Kwon EM, Koopmeiners JS, et al.: Analysis of recently identified prostate cancer susceptibility loci in a population-based study: associations with family history and clinical features. Clin Cancer Res 15 (9): 3231-7, 2009.
162. Berndt SI, Wang Z, Yeager M, et al.: Two susceptibility loci identified for prostate cancer aggressiveness. Nat Commun 6: 6889, 2015.
163. Gao P, Xia JH, Sipeky C, et al.: Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus. Cell 174 (3): 576-589.e18, 2018.
164. Amin Al Olama A, Kote-Jarai Z, Schumacher FR, et al.: A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease. Hum Mol Genet 22 (2): 408-15, 2013.
165. Szulkin R, Karlsson R, Whitington T, et al.: Genome-wide association study of prostate cancer-specific survival. Cancer Epidemiol Biomarkers Prev 24 (11): 1796-800, 2015.
166. Penney KL, Pyne S, Schumacher FR, et al.: Genome-wide association study of prostate cancer mortality. Cancer Epidemiol Biomarkers Prev 19 (11): 2869-76, 2010.
167. Li W, Middha M, Bicak M, et al.: Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival. Eur Urol 74 (6): 710-719, 2018.
168. FitzGerald LM, Zhao S, Leonardson A, et al.: Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases. Prostate Cancer Prostatic Dis 21 (2): 228-237, 2018.

Clinical Application of Genetic Testing for Inherited Prostate Cancer

Criteria for Genetic Testing in Prostate Cancer

The criteria for consideration of genetic testing for prostate cancer susceptibility varies depending on the emerging guidelines and expert opinion consensus as summarized in Table 2.[1,2,3,4,5] Hereditary prostate cancer genetic testing criteria are based on an individual's family history, personal/disease characteristics, and tumor sequencing results. The genes recommended for genetic testing vary based on national guidelines and consensus conference recommendations. The NCCN Prostate Cancer guidelines recommend testing for at least BRCA1, BRCA2, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2 for men meeting specific testing indications.[4] A consensus conference in 2019 addressed the role of genetic testing for inherited prostate cancer.[6] Family history–based indications for testing included testing for BRCA1/BRCA2, HOXB13, DNA mismatch repair (MMR) genes, and ATM. Tumor sequencing with potential findings of germline variants in BRCA1/BRCA2, DNA MMR genes, or ATM as well as other genes, is supported for confirmatory germline testing. Somatic findings for which germline testing is considered include the following:

• Somatic mutations that are associated with germline susceptibility.
• Hypermutated tumors, which are indicative of DNA MMR.
• Chromosome rearrangements in specific tumors.
• High-variant allele frequency (percent of sequence reads that have the identified variant). Variant allele frequency can be altered for reasons not associated with germline variants such as loss of heterozygosity, ploidy (copy number variants), tumor heterogeneity, and tumor sample purity.[7]

Men with metastatic castration-resistant prostate cancer were recommended to undergo genetic testing for BRCA1/BRCA2, DNA MMR genes, and ATM.[6] Another consensus conference focused on advanced prostate cancer stated that among panelists who recommended genetic testing on the basis of various criteria, there was agreement to use large panel testing including homologous recombination and DNA MMR genes.[2] Available genetic testing indications from guidelines and consensus conferences are shown in Table 2.

Table 2. Indications for Genetic Testing for Prostate Cancer Risk

​	Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2020)a[6]	Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2023)b[3]	NCCN Prostate Cancer (Version 3.2022)c[4]	European Advanced Prostate Cancer Consensus Conference (Gillessen et al. 2017[2]and Gillessen 2020[8])d
dMMR = mismatch repair deficient; FDR = first-degree relative; HBOC = hereditary breast and ovarian cancer; MSI = microsatellite instability; NCCN = National Comprehensive Cancer Network; SDR= second-degree relative; TDR= third-degree relative.
a Giri et al.: Specific genes to test includeBRCA1/BRCA2, DNA MMR genes,ATM, andHOXB13depending on various testing indications.
b NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic guidelines state that prostate cancer risk management is indicated forBRCA1andBRCA2carriers, but evidence for risk management is insufficient for other genes.
c NCCN Prostate Cancer guidelines specify that germline multigene testing includes at least the following genes:BRCA1,BRCA2,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6, andPMS2. Including additional genes may be appropriate based on clinical context.
d Gillessen et al. endorsed the use of large panel testing including homologous recombination and DNA MMR genes.
Family History Criteria	All men with prostate cancer from families meeting established testing or syndromic criteria for HBOC, hereditary prostate cancer, or Lynch syndrome	Men affected with prostate cancer who have a family history of the following: ≥1 FDR,SDR, or TDR (on the same side of the family) with breast cancer at age ≤50 y or with any of the following: triple-negative breast cancer, ovarian cancer, pancreatic cancer, high- or very-high-risk prostate cancer, or metastatic prostate cancer at any age	Men affected with prostate cancer who have the following: ≥1 FDR, SDR, or TDR (on the same side of the family) with breast cancer at age ≤50 y, colorectal or endometrial cancer at age ≤50 y, male breast cancer at any age, ovarian cancer at any age, exocrine pancreatic cancer at any age, or metastatic, regional, very-high-risk, high-risk prostate cancer at any age	Men with a positive family history of prostate cancer[2]
	Men affected with prostate cancer who have >2 close biological relatives with a cancer associated with HBOC, hereditary prostate cancer, or Lynch syndrome	Men affected with prostate cancer who have ≥2 FDRs, SDRs, or TDRs (on the same side of the family) with breast cancer or prostate cancer (any grade) at any age	Men affected with prostate cancer who have ≥1 FDR with prostate cancer at age ≤60 y (exclude relatives with clinically localized Grade Group 1 disease)	Men with a positive family history of other cancer syndromes (HBOC and/or pancreatic cancer and/or Lynch syndrome)[2]
	Men with anFDRwho was diagnosed with prostate cancer at <60 y	Men with or without prostate cancer with an FDR who meets any of the criteria listed above (except when a man without prostate cancer has relatives who meet the above criteria solely for systemic therapy decision-making; these criteria may also be extended to an affected TDR if he/she is related to the patient through two male relatives)	Men affected with prostate cancer who have ≥2 FDRs, SDRs, or TDRs (on the same side of the family) with breast cancer or prostate cancer at any age (exclude relatives with clinically localized Grade Group 1 disease)
	Men with relatives who died from prostate cancer		Men affected with prostate cancer who have ≥3 FDRs or SDRs (on the same side of the family) with the following Lynch syndrome-related cancers, especially if diagnosed at age <50 y: colorectal, endometrial, gastric, ovarian, exocrine pancreas, upper tract urothelial, glioblastoma, biliary tract, and small intestine
	Men with a metastatic prostate cancer in an FDR
	Consider genetic testing in men with prostate cancer andAshkenazi Jewishancestry	Men with prostate cancer and Ashkenazi Jewish ancestry	Men with prostate cancer and Ashkenazi Jewish ancestry
			Men with prostate cancer and a known family history of a pathogenic or likely pathogenic variant in one of the following genes:BRCA1,BRCA2,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6,PMS2, orEPCAM
Clinical/Pathological Features	Men with metastatic prostate cancer	Men with metastatic prostate cancer	Men with metastatic prostate cancer	Men with newly diagnosed metastatic prostate cancer (62% of panel voted in favor ofgenetic counseling /testing in a minority of selected patients)[8]
	Men with stage T3a or higher prostate cancer	Men with high- or very-high-risk prostate cancer	Men with high- or very-high-risk prostate cancer
	Men with prostate cancer that has intraductal/ductal histology	Testing may be considered in men who have intermediate-risk prostate cancer with intraductal/cribriform histology at any age	Germline testing may be considered in men who have intermediate-risk prostate cancer with intraductal/cribriform histology
			Germline testing may be considered in men with prostate cancer AND a prior personal history of any of the following cancers: exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal	Men with prostate cancer diagnosed at age <60 y[2]
Tumor Sequencing Characteristics	Men with prostate cancer whose somatic testing reveals the possibility of a germline variant in a cancer risk gene, especiallyBRCA2,BRCA1,ATM, and DNA mismatch repair genes	Men with a pathogenic variant found on tumor genomic testing that may have clinical implications if it is also identified in the germline	Recommend tumor testing forpathogenic variantsin homologous recombination genes in men with metastatic disease; consider tumor testing in men with regional prostate cancer
			RecommendMSI -high or dMMR tumor testing in men with metastatic castration-resistant prostate cancer; consider testing in men with regional or castration-naïve prostate cancer

Multigene (Panel) Testing in Prostate Cancer

Since next-generation sequencing (NGS) has become readily available and patent restrictions have been eliminated, several clinical laboratories now offer multigene panel testing at a cost that is comparable to that of single-gene testing. However, variants of uncertain significance can be found. These results should be viewed with caution, since their clinical significance is unknown. For more information on genetic counseling considerations and research associated with multigene testing, see the Multigene (panel) testing section in Cancer Genetics Risk Assessment and Counseling. The following section gives information about additional genes that may be on hereditary prostate cancer panel tests.

One retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis assessed the incidence of germline pathogenic variants in 16 DNA repair genes. Pathogenic variants were identified in 11.8% (82 of 692), a rate higher than in men with localized prostate cancer (4.6%, P < .001), suggesting that genetic aberrations are more commonly observed in men with aggressive forms of disease.[9] Two studies were published using data from a clinical testing laboratory database. The first study evaluated 1,328 men with prostate cancer and reported an overall pathogenic variant rate of 15.6%, including 10.9% in DNA repair genes.[10] A second study involved a larger cohort of 3,607 men with prostate cancer, some of whom had been included in the prior publication.[11] The reported pathogenic variant rate was 17.2%. Overall, pathogenic variant rates by gene were consistently reported between the two studies and were as follows: BRCA2, 4.74%; CHEK2, 2.88%; ATM, 2.03%; and BRCA1, 1.25%.[11] The most commonly aberrant gene in this cohort was BRCA2. The first publication reported associations between family history of breast cancer and high Gleason score (≥8).[10] The second publication focused on the percentage of men with pathogenic variants who met NCCN national guidelines for genetic testing and found that 229 individuals (37%) with pathogenic variants in this cohort did not meet guidelines for genetic testing.[11] A systematic evidence review examined the median prevalence of pathogenic germline variants in the DNA damage-response pathway, including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. The overall prevalence was 18.6% (range, 17.2%–19%; n = 1,712) for general prostate cancer, 11.6% (range, 11.4%–11.8%; n = 1,261) for metastatic prostate cancer, 8.3% (range, 7.5%–9.1%; n = 738) for metastatic castration-resistant prostate cancer, and 29.3% (range, 7.3%–92.67%; n = 327) for familial prostate cancer.[12]

A case-control study in a Japanese population of 7,636 men with prostate cancer and 12,366 men without prostate cancer evaluated pathogenic variants in eight genes (BRCA1, BRCA2, CHEK2, ATM, NBN, PALB2, HOXB13, and BRIP1) for an association with prostate cancer.[13] The study found strong associations for BRCA2 (odds ratio [OR], 5.65; 95% confidence interval [CI], 3.55–9.32), HOXB13 (OR, 4.73; 95% CI, 2.84–8.19), and ATM (OR, 2.86; 95% CI, 1.63–5.15). The study supports a population-specific assessment of the genetic contribution to prostate cancer risk.

Genetic Testing for Prostate Cancer Risk Assessment

Genetic testing for pathogenic variants in prostate cancer risk genes is now available. This can identify men at increased prostate cancer risk. Research from selected cohorts has reported that prostate cancer risk is elevated in men with pathogenic variants in the BRCA1 gene, the BRCA2 gene, and on a smaller scale, the MMR genes. In addition, pathogenic variants in HOXB13 account for a small proportion of hereditary prostate cancer cases. This section summarizes the evidence for the genes mentioned above and additional genes that may be on prostate cancer susceptibility panel tests.

BRCA1andBRCA2

Studies of male carriers of BRCA1[14] and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[15] Prostate cancer, in particular, has been observed at higher rates in male carriers of BRCA2 pathogenic variants than in the general population.[16] For more information about BRCA1 and BRCA2 pathogenic variants, see BRCA1 and BRCA2: Cancer Risks and Management.

BRCA–associated prostate cancer risk

The risk of prostate cancer in carriers of BRCA pathogenic variants has been studied in various settings.

In an effort to clarify the relationship between BRCA pathogenic variants and prostate cancer risk, findings from several case series are summarized in Table 3.

Table 3. Case Series ofBRCAPathogenic Variants in Prostate Cancer

Study	Population	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)
BCLC = Breast Cancer Linkage Consortium; CDC = Centers for Disease Control and Prevention; CI = confidence interval; CIMBA = Consortium of Investigators of Modifiers ofBRCA1/2; OCCR = Ovarian Cancer Cluster Region; RR = relative risk; SIR = standardized incidence ratio.
a Includes all cancers except breast, ovarian, and nonmelanoma skin cancers.
BCLC (1999)[17]	BCLC family set that included 173BRCA2linkage – or pathogenic variant–positive families, among which there were 3,728 individuals and 333 cancersa	Not assessed	Overall: RR, 4.65 (95% CI, 3.48–6.22)
			Men <65 y: RR, 7.33 (95% CI, 4.66–11.52)
Thompson et al. (2001)[18]	BCLC family set that included 164BRCA2pathogenic variant–positive families, among which there were 3,728 individuals and 333 cancersa	Not assessed	OCCR: RR, 0.52 (95% CI, 0.24–1.00)
Thompson et al. (2002)[14]	BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were carriers ofBRCA1pathogenic variants; 1,106 were testednoncarriers, and 8,496 were not tested	Overall: RR, 1.07 (95% CI, 0.75–1.54)	Not assessed
		Men younger than 65 y: RR, 1.82 (95% CI, 1.01–3.29)
Mersch et al. (2015)[16]	Clinical genetics population at a single institution from 1997–2013. Compared cancer incidence with U.S. Statistics Report by CDC for general population cancer incidence	SIR, 3.809 (95% CI, 0.766–11.13) (Not significant)	SIR, 4.89 (95% CI, 1.959–10.075)
Silvestri et al. (2020)[19]	Cohort of 6,902 men who carried pathogenic variants inBRCA1orBRCA2in 53 cancer genetics groups across 33 countries	Occurred in 22.3% of carriers	Occurred in 25.6% of carriers
Li et al. (2022)[20]	Cohort of 3,184BRCA1and 2,157BRCA2families from CIMBA; 34 of 1,508 men withBRCA1pathogenic variants and 71 of 1,063 men withBRCA2pathogenic variants had prostate cancer	RR, 0.82 (95% CI, 0.54–1.27)	RR, 2.22 (95% CI, 1.63–3.03)

Estimates derived from the Breast Cancer Linkage Consortium may be overestimates because the data were generated from highly selected families that had significant risks of breast and ovarian cancers and were suitable for linkage analysis. A review of the relationship between BRCA2 germline pathogenic variants and prostate cancer risk suggests that BRCA2 confers a significant increase in risk among male members of HBOC families but likely plays only a small role in site-specific, multiple-case prostate cancer families.[21]

A meta-analysis assessed the relationship between BRCA1 and BRCA2 germline pathogenic variants and prostate cancer risk. The risk of prostate cancer was higher in BRCA2 carriers (OR, 2.64; 95% CI, 2.03–3.47) than in BRCA1 carriers (OR, 1.35; 95% CI, 1.03–1.76).[22] Several studies cited in Table 3 were included in this meta-analysis.

Prevalence ofBRCAfounder pathogenic variants in men with prostate cancer

Ashkenazi Jewish population

Several studies in Israel and in North America have analyzed the frequency of BRCAfounder pathogenic variants among Ashkenazi Jewish (AJ) men with prostate cancer.[23,24,25] Two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic variant (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these pathogenic variants in the general Jewish population are 0.9% (95% CI, 0.7%–1.1%) for the 185delAG pathogenic variant, 0.3% (95% CI, 0.2%–0.4%) for the 5382insC pathogenic variant, and 1.3% (95% CI, 1.0%–1.5%) for the BRCA2 6174delT pathogenic variant.[26,27,28,29] In these studies, the relative risks (RRs) were commonly greater than 1, but only a few were statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder pathogenic variants.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia area who carried one of the BRCA Ashkenazi founder pathogenic variants. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4%–30%) among carriers of the founder pathogenic variants and 3.8% (95% CI, 3.3%–4.4%) among noncarriers.[29] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female carriers at the same age (16% by age 70 y; 95% CI, 6%–28%). The risk of prostate cancer in male carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder pathogenic variants. Prostate cancer risk differed depending on the gene, with BRCA1 pathogenic variants associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 pathogenic variant began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

The studies summarized in Table 4 used similar case-control methods to examine the prevalence of Ashkenazi founder pathogenic variants among Jewish men with prostate cancer and found an overall positive association between carrier status of founder pathogenic variants and prostate cancer risk.

Table 4. Case-Control Studies in Ashkenazi Jewish Populations ofBRCA1andBRCA2and Prostate Cancer Risk

Study	Cases/Controls	Pathogenic Variant Frequency (BRCA1)	Pathogenic Variant Frequency (BRCA2)	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; MECC = Molecular Epidemiology of Colorectal Cancer; OR = odds ratio; WAS = Washington Ashkenazi Study.
Giusti et al. (2003)[30]	Cases: 979 consecutive AJ men from Israel diagnosed with prostate cancer between 1994 and 1995	Cases: 16 (1.7%)	Cases: 14 (1.5%)	185delAG: OR, 2.52 (95% CI, 1.05–6.04)	OR, 2.02 (95% CI, 0.16–5.72)	There was no evidence of unique or specific histopathology findings within the pathogenic variant–associated prostate cancers
	Controls: Prevalence of founder pathogenic variants compared with age-matched controls >50 y with no history of prostate cancer from the WAS study and the MECC study from Israel	Controls: 11 (0.81%)	Controls: 10 (0.74%	5282insC: OR, 0.22 (95% CI, 0.16–5.72)
Kirchoff et al. (2004)[31]	Cases: 251 unselected AJ men treated for prostate cancer between 2000 and 2002	Cases: 5 (2.0%)	Cases: 8 (3.2%)	OR, 2.20 (95% CI, 0.72–6.70)	OR, 4.78 (95% CI, 1.87–12.25)
	Controls: 1,472 AJ men with no history of cancer	Controls: 12 (0.8%)	Controls: 16 (1.1%)
Agalliu et al. (2009)[32]	Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis: 1996)	Cases: 12 (1.2%)	Cases: 18 (1.9%)	OR, 1.39 (95% CI, 0.60–3.22)	OR, 1.92 (95% CI, 0.91–4.07)	Gleason score 7–10 prostate cancer was more common in carriers ofBRCA1pathogenic variants (OR, 2.23; 95% CI, 0.84–5.86) and carriers ofBRCA2pathogenic variants (OR, 3.18; 95% CI, 1.62–6.24) than in controls
	Controls: 1,251 AJ men with no history of cancer	Controls: 11 (0.9%)	Controls: 12 (1.0%)
Gallagher et al. (2010)[33]	Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007	Noncarriers: 806 (96.9%)	Noncarriers: 447 (98.5%)	OR, 0.38 (95% CI, 0.05–2.75)	OR, 3.18 (95% CI, 1.52–6.66)	TheBRCA15382insC founder pathogenic variant was not tested in this series, so it is likely that some carriers of this pathogenic variant were not identified. Consequently,BRCA1-related risk may be underestimated. Gleason score 7–10 prostate cancer was more common in carriers ofBRCA2pathogenic variants (85%) than in noncarriers (57%);P = .0002. Carriers ofBRCA1/BRCA2pathogenic variants had significantly greater risk of recurrence and prostate cancer–specific death than did noncarriers
		Cases: 6 (0.7%)	Cases: 20 (2.4%)
	Controls: 454 AJ men with no history of cancer	Controls: 4 (0.9%)	Controls: 3 (0.7%)

These studies support the hypothesis that prostate cancer occurs excessively among carriers of AJ founder pathogenic variants and suggest that the risk may be greater among men with the BRCA2 founder pathogenic variant (6174delT) than among those with one of the BRCA1 founder pathogenic variants (185delAG; 5382insC). The magnitude of the BRCA2-associated risks differs somewhat, undoubtedly because of interstudy differences related to participant ascertainment, calendar time differences in diagnosis, and analytic methods. Some data suggest that BRCA-related prostate cancer has a significantly worse prognosis than prostate cancer that occurs among noncarriers.[33]

Other populations

The association between prostate cancer and pathogenic variants in BRCA1 and BRCA2 has also been studied in other populations. Table 5 summarizes studies that used case-control methods to examine the prevalence of BRCA pathogenic variants among men with prostate cancer from other varied populations.

Table 5. Case-Control Studies in Varied Populations ofBRCA1andBRCA2and Prostate Cancer Risk

Study	Cases/Controls	Pathogenic Variant Frequency (BRCA1)	Pathogenic Variant Frequency (BRCA2)	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)	Comments
CI = confidence interval; OR = odds ratio; RR = relative risk; SIR = standardized incidence ratio.
Johannesdottir et al. (1996)[34]	Cases: 75 Icelandic men diagnosed with prostate cancer <65 y, between 1983 and 1992, with available archival tissue blocks	Not assessed	Cases: 999del5 (2.7%)	Not assessed	999del5: RR, 2.5 (95% CI, 0.49–18.4)
	Controls: 499 randomly selected DNA samples from the Icelandic National Diet Survey		Controls: (0.4%)
Eerola et al. (2001)[35]	Cases: 107 Finnish hereditary breast cancer families defined as having three first- or second-degree relatives with breast or ovarian cancer at any age	Not assessed	Not assessed	SIR, 1.0 (95% CI, 0.0–3.9)	SIR, 4.9 (95% CI, 1.8–11.0)
	Controls: Finnish population based on gender, age, and calendar period–specific incidence rates
Cybulski et al. (2013)[36]	Cases: 3,750 Polish men with prostate cancer unselected for age or family history and diagnosed between 1999 and 2012	Cases: 14 (0.4%)	Not assessed	AnyBRCA1pathogenic variant: OR, 0.9 (95% CI, 0.4–1.8)	Not assessed	Prostate cancer risk was greater in familial cases and cases diagnosed <60 y
				4153delA: OR, 5.3 (95% CI, 0.6–45.2)
	Controls: 3,956 Polish men with no history of cancer aged 23–90 y	Controls: 17 (0.4%)		5382insC: OR, 0.5 (95% CI, 0.2–1.3)
				C61G: OR, 1.1 (95% CI, 1.6–2.2)

These data suggest that prostate cancer risk in carriers of BRCA1/BRCA2 pathogenic variants varies with the location of the pathogenic variant (i.e., there is a correlation between genotype and phenotype).[34,35,37] These observations might explain some of the inconsistencies encountered in prior studies of these associations, because varied populations may have differences in the proportion of individuals with specific BRCA1/BRCA2 pathogenic variants.

Several case series have also explored the role of BRCA1 and BRCA2 pathogenic variants and prostate cancer risk.

Table 6. Case Series ofBRCA1andBRCA2and Prostate Cancer Risk

Study	Population	Pathogenic Variant Frequency (BRCA1)	Pathogenic Variant Frequency (BRCA2)	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)	Comments
CI = confidence interval; MLPA = multiplex ligation-dependent probe amplification; RR = relative risk; SIR = standardized incidence ratio; UK = United Kingdom.
a Estimate calculated using RR data in UK general population.
b Risks calculated on men with pathogenic variants diagnosed with prostate cancer.
Agalliu et al. (2007)[38]	290 men (White, n = 257; African American, n = 33) diagnosed with prostate cancer <55 y and unselected for family history	Not assessed	2 (0.69%)	Not assessed	RR, 7.8 (95% CI, 1.8–9.4)	No pathogenic variants were found in African American men
						The two men with a pathogenic variant reported no family history of breast cancer or ovarian cancer
Agalliu et al. (2007)[39]	266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; the median age at prostate cancer diagnosis was 58 y	Not assessed	0 (0%)	Not assessed	Not assessed	31 nonsynonymous variations were identified; no truncating or pathogenic variants were detected
Tryggvadóttir et al. (2007)[40]	527 men diagnosed with prostate cancer between 1955 and 2004	Not assessed	30/527 (5.7%) carried the Icelandic founder pathogenic variant 999del5	Not assessed	Not assessed	TheBRCA2999del5 pathogenic variant was associated with a lower mean age at prostate cancer diagnosis (69 vs. 74 y;P = .002)
Kote-Jarai et al. (2011)[41]	1,832 men diagnosed with prostate cancer between ages 36 and 88 y who participated in the UK Genetic Prostate Cancer Study	Not assessed	Overall: 19/1,832 (1.03%)	Not assessed	RR, 8.6a(95% CI, 5.1–12.6)	MLPA was not used; therefore, the pathogenic variant frequency may be an underestimate, given the inability to detect large genomic rearrangements
			Prostate cancer diagnosed ≤55 y: 8/632 (1.27%)
Leongamornlert et al. (2012)[42]	913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; this included 821 cases diagnosed between ages 36 and 65 y, regardless of family history, and 92 cases diagnosed >65 y with a family history of prostate cancer	All cases: 4/886 (0.45%)	Not assessed	RR, 3.75a(95% CI, 1.02–9.6)	Not assessed	Quality-control assessment after sequencing excluded 27 cases, resulting in 886 cases included in the final analysis
		Cases ≤65 y: 3/802 (0.37%)
Nyberg et al. (2019)[43]	Prospective cohort of men withBRCA1(n = 376) orBRCA2(n = 447) pathogenic variants from the UK and Ireland; the median follow-up was 5.9 y and 5.3 y, respectively, for prostate cancer diagnoses	Confirmed pathogenic variant: 16/376	Confirmed pathogenic variant: 26/447	SIR, 2.35 (95% CI, 1.43–3.88)	SIR, 4.45 (95% CI, 2.99–6.61)	Absolute prostate cancer risksb: 21% (95% CI, 13%–34%) by age 75 y and 29% (95% CI, 17%–45%) by age 85 y forBRCA1; 27% (95% CI, 17%–41%) by age 75 y and 60% (95% CI, 43%–78%) by age 85 y forBRCA2

These case series confirm that pathogenic variants in BRCA1 and BRCA2 do not play a significant role in hereditary prostate cancer. However, germline pathogenic variants in BRCA2 account for some cases of early-onset prostate cancer, although this is estimated to be less than 1% of early-onset prostate cancers in the United States.[38]

Prostate cancer aggressiveness in carriers ofBRCApathogenic variants

The studies summarized in Table 7 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 pathogenic variant.

Table 7. Case-Control Studies ofBRCA1andBRCA2and Prostate Cancer Aggressiveness

Study	Cases / Controls	Gleason Scorea	PSAa	Tumor Stage or Gradea	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OR = odds ratio; PSA = prostate-specific antigen; UK = United Kingdom.
a Measures of prostate cancer aggressiveness.
Tryggvadóttir et al. (2007)[40]	Cases: 30 men diagnosed with prostate cancer who were carriers ofBRCA2999del5 founder pathogenic variants	Gleason score 7–10:	Not assessed	Stage IV at diagnosis:
		— Cases: 84%		— Cases: 55.2%
	Controls: 59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry theBRCA2999del5 pathogenic variant	— Controls: 52.7%		— Controls: 24.6%
Agalliu et al. (2009)[32]	Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis, 1996)	Gleason score 7–10:	Not assessed	Not assessed
		—BRCA1185delAG pathogenic variant: OR, 3.54 (95% CI, 1.22–10.31)
	Controls: 1,251 AJ men with no history of cancer	—BRCA26174delT pathogenic variant: OR, 3.18 (95% CI, 1.37–7.34)
Edwards et al. (2010)[44]	Cases: 21 men diagnosed with prostate cancer who harbored aBRCA2 pathogenic variant; 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series	Not assessed	PSA ≥25 ng/mL: HR, 1.39 (95% CI, 1.04–1.86)	Stage T3: HR, 1.19 (95% CI, 0.68–2.05)
				Stage T4: HR, 1.87 (95% CI, 1.00–3.48)
				Grade 2: HR, 2.24 (95% CI, 1.03–4.88)
	Controls: 1,587 age- and stage-matched men with prostate cancer			Grade 3: HR, 3.94 (95% CI, 1.78–8.73)
Gallagher et al. (2010)[33]	Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 carriers ofBRCA1pathogenic variants and 20 carriers ofBRCA2pathogenic variants	Gleason score 7–10:	Not assessed	Not assessed	TheBRCA15382insC founder pathogenic variant was not tested in this series
	Controls: 454 AJ men with no history of cancer	—BRCA26174delT pathogenic variant: HR, 2.63 (95% CI, 1.23–5.6;P = .001)
Thorne et al. (2011)[45]	Cases: 40 men diagnosed with prostate cancer who were carriers of BRCA2 pathogenic variants from 30 familial breast cancer families from Australia and New Zealand	Gleason score ≥8:	PSA 10–100 ng/mL:	Stage ≥pT3 at presentation:	Carriers ofBRCA2pathogenic variants were more likely to have high-risk disease byD'Amico criteriathan were noncarriers (77.5% vs. 58.7%,P = .05)
			—BRCA2pathogenic variants: 35% (14/40)	—BRCA2pathogenic variants: 44.7% (17/38)
		—BRCA2pathogenic variants: 65.8% (25/38)	— Controls: 27.9% (27/97)
			PSA >101 ng/mL:
	Controls: 97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and noBRCApathogenic variant found in the family	— Controls: 33.0% (25/97)	—BRCA2pathogenic variants: 10% (4/40)	— Controls: 22.6% (21/97)
			— Controls: 2.1% (2/97)
Castro et al. (2013)[46]	Cases: 2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers ofBRCA1pathogenic variants and 61 were carriers ofBRCA2pathogenic variants	Gleason score >8:	BRCA1median PSA: 8.9 (range, 0.7–3,000)	Stage ≥pT3 at presentation:	Nodal metastasis and distant metastasis were higher in men with aBRCApathogenic variant than in controls
		—BRCA1pathogenic variants: 27.8% (5/18)		—BRCA1: 38.9% (7/18)
		—BRCA2pathogenic variants: 37.7% (23/61)	BRCA2 median PSA: 15.1 (range, 0.5–761)	—BRCA2 : 49.2% (30/61)
	Controls: 1,940 men who wereBRCA1/BRCA2noncarriers	— Controls 15.4% (299/1,940)	Controls median PSA: 11.3 (range, 0.2–7,800)	— Controls: 31.7% (616/1,940)
Akbari et al. (2014)[47]	Cases: 4,187 men who underwent prostate biopsy for elevated PSA or abnormal exam, including 26 men with at least oneBRCAcoding pathogenic variant (all 26 codingexonsofBRCAwere sequenced forpolymorphisms)	Gleason score 7–10:	Cases median PSA: 56.3	Not fully assessed in cases and controls	The 12-year survival for men with aBRCA2pathogenic variant was inferior to that of men without aBRCA2pathogenic variant (61.8% vs. 94.3%;P< 10−4). Among the men with high-grade disease (Gleason 7–9), the presence of aBRCA2pathogenic variant was associated with an HR of 4.38 (95% CI, 1.99–9.62;P< .0001) after adjusting for age and PSA level
		— Cases 96%
	Controls: 1,878 men with noBRCAcoding pathogenic variants (all 26 coding exons ofBRCAwere sequenced for polymorphisms)	— Controls 54%	Controls median PSA: 13.3

Men harboring pathogenic variants in the United Kingdom and Ireland were prospectively followed for prostate cancer diagnoses (BRCA1 [n = 16/376] and BRCA2 [n = 26/447]; median follow-up, 5.9 y and 5.3 y, respectively).[43] The prostate cancers identified covered the spectrum of Gleason scores from less than 6 to greater than 8; however, they differed by gene:

• BRCA1 Gleason score less than 6; standardized incidence ratio (SIR), 3.50 (95% CI, 1.67–7.35) and Gleason score greater than 7; SIR, 1.80 (95% CI, 0.89–3.65).
• BRCA2 Gleason score less than 6; SIR, 3.03 (95% CI, 1.24–7.44) and Gleason score greater than 7; SIR, 5.07 (95% CI, 3.20–8.02).

These studies suggest that prostate cancer in BRCA pathogenic variant carriers may be associated with aggressive disease features including a high Gleason score, a high prostate-specific antigen (PSA) level at diagnosis, and a high tumor stage and/or grade at diagnosis. This is a finding that warrants consideration when patients undergo cancer risk assessment and genetic counseling.[3] Research is under way to gain insight into the biologic basis of aggressive prostate cancer in carriers of BRCA pathogenic variants. One study of 14 BRCA2 germline pathogenic variant carriers reported that BRCA2-associated prostate cancers harbor increased genomic instability and a mutational profile that more closely resembles metastatic prostate cancer than localized disease, with genomic and epigenomic dysregulation of the MED12L/MED12 axis similar to metastatic castration-resistant prostate cancer.[48]

BRCA1/BRCA2and survival outcomes

Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 pathogenic variants have been examined for survival. In an unadjusted analysis performed on a case series, median survival was 4 years in 183 men with prostate cancer with a BRCA2 pathogenic variant and 8 years in 119 men with a BRCA1 pathogenic variant. The study suggests that carriers of BRCA2 pathogenic variants have a poorer survival than carriers of BRCA1 pathogenic variants.[49] The case-control studies summarized in Table 8 further assess this observation.

Table 8. Case-Control Studies ofBRCA1andBRCA2and Survival Outcomes

Study	Cases	Controls	Prostate Cancer–Specific Survival	Overall Survival	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen; UK = United Kingdom.
Tryggvadóttir et al. (2007)[40]	30 men diagnosed with prostate cancer who were carriers ofBRCA2999del5 founder pathogenic variants	59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry theBRCA2999del5 pathogenic variant	BRCA2999del5 pathogenic variant was associated with a higher risk of death from prostate cancer (HR, 3.42; 95% CI, 2.12–5.51), which remained after adjustment for tumor stage and grade (HR, 2.35; 95% CI, 1.08–5.11)	Not assessed
Edwards et al. (2010)[44]	21 men diagnosed with prostate cancer who harbored aBRCA2pathogenic variant: 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series	1,587 age- and stage-matched men with prostate cancer	Not assessed	Overall survival was lower in carriers ofBRCA2pathogenic variants (4.8 y) than in noncarriers (8.5 y); in noncarriers, HR, 2.14 (95% CI, 1.28–3.56;P = .003)
Gallagher et al. (2010)[33]	832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which 6 were carriers ofBRCA1pathogenic variants and 20 carriers ofBRCA2pathogenic variants	454 AJ men with no history of cancer	After adjusting for stage, PSA, Gleason score, and therapy received:	Not assessed	TheBRCA15382insC founder pathogenic variant was not tested in this series
			– Carriers ofBRCA1 185delAG pathogenic variants had a greater risk of death due to prostate cancer (HR, 5.16; 95% CI, 1.09–24.53;P = .001)
			— Carriers of BRCA26174delT pathogenic variants had a greater risk of death due to prostate cancer (HR, 5.48; 95% CI, 2.03–14.79;P = .001)
Thorne et al. (2011)[45]	40 men diagnosed with prostate cancer who were carriers of BRCA2 pathogenic variants from 30 familial breast cancer families from Australia and New Zealand	97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and noBRCApathogenic variant found in the family	BRCA2carriers were shown to have an increased risk of prostate cancer–specific mortality (HR, 4.5; 95% CI, 2.12–9.52;P = 8.9 × 10-5), compared with noncarrier controls	BRCA2carriers were shown to have an increased risk of death (HR, 3.12; 95% CI, 1.64–6.14;P = 3.0 × 10-4), compared with noncarrier controls	There were too fewBRCA1carriers available to include in the analysis
Castro et al. (2013)[46]	2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers ofBRCA1pathogenic variants and 61 were carriers ofBRCA2pathogenic variants	1,940 men who wereBRCA1/BRCA2noncarriers	Prostate cancer–specific survival at 5 y:	Overall survival at 5 y:	For localized prostate cancer, metastasis-free survival was also higher in controls than in carriers of pathogenic variants (93% vs. 77%; HR, 2.7)
			— BRCA1: 80.8% (95% CI, 56.9%–100%)	— BRCA1: 82.5% (95% CI, 60.4%–100%)
			—BRCA2: 67.9% (95% CI 53.4%–82.4%)	—BRCA2: 57.9% (95% CI, 43.4%–72.4%)
			— Controls: 90.6% (95% CI 88.8%–92.4%)	— Controls: 86.4% (95% CI, 84.4%–88.4%)
Castro et al. (2015)[50]	1,302 men from the UK with local or locally advanced prostate cancer, including 67 carriers ofBRCA1/BRCA2pathogenic variants	1,235 men who wereBRCA1/BRCA2noncarriers	Prostate cancer–specific survival:	Not assessed
			—BRCA1/BRCA2: 61% at 10 y
			— Noncarriers: 85% at 10 y

These findings suggest overall survival (OS) and prostate cancer–specific survival may be lower in carriers of pathogenic variants than in controls.

Additional studies involving theBRCAregion

A genome-wide scan for hereditary prostate cancer in 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence of linkage to chromosome 17q markers.[51] The maximum logarithm of the odds (LOD) score in all families was 2.36, and the LOD score increased to 3.27 when only families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for pathogenic variants using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[52] Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancers was found to have a truncating pathogenic variant (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence of a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating variants in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.

Another study from the UM-PCGP examined common genetic variation in BRCA1.[53] Conditional logistic regression analysis and family-based association tests were performed in 323 familial prostate cancer families and early-onset prostate cancer families, which included 817 men with and without the disease, to investigate the association of SNVs tagging common haplotype variation in a 200-kb region surrounding and including BRCA1. Three SNVs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNV rs1799950 (OR, 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNV rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[51]

HOXB13

Summary

HOXB13 was the first gene found to be associated with hereditary prostate cancer. The HOXB13 G84E variant has been extensively studied because of its association with prostate cancer risk.

• Overall risk of prostate cancer with the G84E variant ranges from 3- to 5-fold, with a higher risk of early-onset prostate cancer with the G84E variant of up to 10-fold.
• Penetrance for carriers of the G84E variant is an approximate 60% lifetime risk of prostate cancer by age 80 years.
• There is no clear association of the G84E variant with aggressive prostate cancer or other cancers.
• Preliminary studies suggest additional variants in HOXB13 may be relevant for prostate cancer risk in diverse populations.

Background

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[51] Fine-mapping of this region provided strong evidence of linkage (LOD score, 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger.[54] The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins University).[55]Probands from four families were discovered to have a recurrent pathogenic variant (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the pathogenic variant. The pathogenic variant status was determined in 5,083 additional cases and 2,662 controls. Carrier frequencies and ORs for prostate cancer risk were as follows:

• Men with a positive family history of prostate cancer, 2.2% versus negative, 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10^-4).
• Men younger than 55 years at diagnosis, 2.2% versus older than 55 years, 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10^-4).
• Men with a positive family history of prostate cancer and younger than 55 years at diagnosis, 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years, 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10^-6).
• Men with a positive family history of prostate cancer and older than 55 years at diagnosis, 1.2%.
• Controls, 0.1% to 0.2%.[55]

Validation and confirmatory studies

A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[56] Within carrier families, the G84E pathogenic variant was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E pathogenic variant was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10^-6).

Additional studies have emerged that better define the carrier frequency and prostate cancer risk associated with the HOXB13 G84E pathogenic variant.[55,57,58,59,60,61,62] This pathogenic variant appears to be restricted to White men, primarily of European descent.[55,57,58,59] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases.[60] A pooled analysis of European Americans that included 9,016 cases and 9,678 controls found an overall G84E pathogenic variant frequency of 1.34% among cases and 0.28% among controls.[61]

Risk of prostate cancer by HOXB13 G84E pathogenic variant status has been reported to vary by age of onset, family history, and geographical region. A validation study in an independent cohort of 9,988 cases and 61,994 controls from six studies of men of European ancestry, including 4,537 cases and 54,444 controls from Iceland whose genotypes were largely imputed, reported an OR of 7.06 (95% CI, 4.62–10.78; P = 1.5 × 10⁻¹⁹) for prostate cancer risk by G84E carrier status.[63] A pooled analysis reported a prostate cancer OR of 4.86 (95% CI, 3.18–7.69; P = 3.48 × 10^-17) in men with HOXB13 pathogenic variants compared with noncarriers; this increased to an OR of 8.41 (95% CI, 5.27–13.76; P = 2.72 ×10^-22) among men diagnosed with prostate cancer at age 55 years or younger. The OR was 7.19 (95% CI, 4.55–11.67; P = 9.3 × 10^-21) among men with a positive family history of prostate cancer and 3.09 (95% CI, 1.83–5.23; P = 6.26 × 10^-6) among men with a negative family history of prostate cancer.[61] A meta-analysis that included 24,213 cases and 73,631 controls of European descent revealed an overall OR for prostate cancer by carrier status of 4.07 (95% CI, 3.05–5.45; P < .00001). Risk of prostate cancer varied by geographical region: United States (OR, 5.10; 95% CI, 3.21–8.10; P < .00001), Canada (OR, 5.80; 95% CI, 1.27–26.51; P = .02), Northern Europe (OR, 3.61; 95% CI, 2.81–4.64; P < .00001), and Western Europe (OR, 8.47; 95% CI, 3.68–19.48; P < .00001).[58] In addition, the association between the G84E pathogenic variant and prostate cancer risk was higher for early-onset cases (OR, 10.11; 95% CI, 5.97–17.12). There was no significant association with aggressive disease in the meta-analysis.

Another meta-analysis that included 11 case-control studies also reported higher risk estimates for prostate cancer in HOXB13 G84E carriers (OR, 4.51; 95% CI, 3.28–6.20; P < .00001) and found a stronger association between HOXB13 G84E and early-onset disease (OR, 9.73; 95% CI, 6.57–14.39; P < .00001).[64] An additional meta-analysis of 25 studies that included 51,390 cases and 93,867 controls revealed an OR for prostate cancer of 3.248 (95% CI, 2.121–3.888). The association was most significant in White individuals (OR, 2.673; 95% CI, 1.920–3.720), especially those of European descent. No association was found for breast or colorectal cancer.[65] One population-based, case-control study from the United States confirmed the association of the G84E pathogenic variant with prostate cancer (OR, 3.30; 95% CI, 1.21–8.96) and reported a suggestive association with aggressive disease.[66] In addition, one study identified no men of AJ ancestry who carried the G84E pathogenic variant.[67] A case-control study from the United Kingdom that included 8,652 cases and 5,252 controls also confirmed the association of HOXB13 G84E with prostate cancer (OR, 2.93; 95% CI, 1.94–4.59; P = 6.27 × 10^-8).[68] The risk was higher among men with a family history of the disease (OR, 4.53; 95% CI, 2.86–7.34; P = 3.1 × 10⁻⁸) and in early-onset prostate cancer (diagnosed at age 55 y or younger) (OR, 3.11; 95% CI, 1.98–5.00; P = 6.1 × 10⁻⁷). No association was found between carrier status and Gleason score, cancer stage, OS, or cancer-specific survival.

However, a 2018 publication of a study combining multiple prostate cancer cases and controls of Nordic origin along with functional analysis reported that simultaneous presence of HOXB13 (G84E) and CIP2A (R229Q) predisposes men to an increased risk of prostate cancer (OR, 21.1; P = .000024).[69] Furthermore, dual carriers had elevated risk for high Gleason score (OR, 2.3; P = .025) and worse prostate cancer–specific survival (HR, 3.9; P = .048). Clinical validation is needed.

Diverse populations

A study of Chinese men with and without prostate cancer failed to identify the HOXB13 G84E pathogenic variant; however, there was an excess of a novel variant, G135E, in cases compared with controls.[70] A large study of approximately 20,000 Japanese men with and without prostate cancer identified another novel HOXB13 variant, G132E, which was associated with prostate cancer with an OR of 6.08 (95% CI, 3.39–11.59).[13]

Two studies confirmed the association between the HOXB13 X285K variant and increased prostate cancer risk in African American men after this variant was identified in Martinique.[71] One of these was a single-institution study, which sequenced HOXB13 in a clinical patient population of 1,048 African American men undergoing prostatectomy for prostate cancer.[72] The HOXB13 X285K variant was identified in eight patients. In a case–case analysis, X285K variant carriers were at increased risk of developing clinically significant prostate cancer (1.2% X285K carrier rate in prostate cancers with a Gleason score ≥7 vs. 0% X285K carrier rate in prostate cancers with Gleason score <7; P = .028). Similarly, X285K variant carriers also had an increased chance of developing prostate cancer at an early age (2.4% X285K carrier rate in patients <50 years vs. 0.5% X285K carrier rate in patients ≥50 years; OR, 5.25; 95% CI, 1.00–28.52; P = .03). A second study included 11,688 prostate cancer cases and 10,673 controls from multiple large consortia.[73] The HOXB13 X285K variant was only present in men of West African ancestry and was associated with a 2.4-fold increased chance of developing prostate cancer (95% CI, 1.5–3.9; P = 2 x 10^-4). Individuals with the X285K variant were also more likely to have aggressive and advanced prostate cancer (Gleason score ≥8: OR, 4.7; 95% CI, 2.3–9.5; P = 2 x 10^-5; stage T3/T4: OR, 4.5; 95% CI, 2.0–10.0; P = 2 x 10^-4; metastatic disease: OR, 5.1; 95% CI, 1.9–13.7; P = .001). This information is important to consider when developing genetic tests for HOXB13 pathogenic variants in broader populations.

Penetrance

Penetrance estimates for prostate cancer development in carriers of the HOXB13 G84E pathogenic variant are also being reported. One study from Sweden estimated a 33% lifetime risk of prostate cancer among G84E carriers.[74] Another study from Australia reported an age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.[75] A study in the United Kingdom that included HOXB13 genotype data from nearly 12,000 men with prostate cancer enrolled between 1993 and 2014 reported that the average predicted risk of prostate cancer by age 85 years is 62% (95% CI, 47%–76%) for carriers of the G84E pathogenic variant. The risk of developing prostate cancer in variant carriers increased if the men had affected family members, especially those diagnosed at an early age.[76]

Biology

HOXB13 plays a role in prostate cancer development and interacts with the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene identified to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility and implications for genetic counseling regarding HOXB13 G84E or other pathogenic variants have yet to be defined.

Mismatch repair (MMR) genes

Five genes are implicated in MMR, namely MLH1, MSH2, MSH6, PMS2, and EPCAM. Germline pathogenic variants in these five genes have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in families, including endometrial, ovarian, duodenal cancers, and transitional cell cancers of the ureter and renal pelvis. For more information about other cancers that are associated with Lynch syndrome, see the Lynch syndrome section in Genetics of Colorectal Cancer. Reports have suggested that prostate cancer may be observed in men harboring an MMR gene pathogenic variant.[77,78] The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male carriers of MMR gene pathogenic variants or obligate carriers.[79] The expected number of cases among these 106 men was 1.52 (P < .01); the men were younger at the time of diagnosis (60.4 y vs. 66.6 y; P = .006) and had more evidence of Gleason score of 8 to 10 (P < .00001) than the cases from the Norwegian Cancer Registry. Kaplan-Meier analysis revealed that the cumulative risk of prostate cancer diagnosis by age 70 years was 30% in carriers of MMR gene pathogenic variants and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNVs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer.[80] To assess the contribution of prostate cancer as a feature of Lynch syndrome, one study performed microsatellite instability (MSI) testing on prostate cancer tissue blocks from families enrolled in a prostate cancer family registry who also reported a history of colon cancer. Among 35 tissue blocks from 31 distinct families, two tumors from families with MMR gene pathogenic variants were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer.[81] Other studies are attempting to characterize rates of prostate cancer in Lynch syndrome families and correlate molecular features with prostate cancer risk.[82]

One study that included two familial cancer registries found an increased cumulative incidence and risk of prostate cancer among 198 independent families with MMR gene pathogenic variants and Lynch syndrome.[83] The cumulative lifetime risk of prostate cancer (to age 80 y) was 30.0% (95% CI, 16.54%–41.30%; P = .07) in carriers of MMR gene pathogenic variants, whereas it was 17.84% in the general population, according to the Surveillance, Epidemiology, and End Results (SEER) Program estimates. There was a trend of increased prostate cancer risk in carriers of pathogenic variants by age 50 years, where the risk was 0.64% (95% CI, 0.24%–1.01%; P = .06), compared with a risk of 0.26% in the general population. Overall, the hazard ratio (HR) (to age 80 y) for prostate cancer in carriers of MMR gene pathogenic variants in the combined data set was 1.99 (95% CI, 1.31–3.03; P = .0013). Among men aged 20 to 59 years, the HR was 2.48 (95% CI, 1.34–4.59; P = .0038).

A systematic review and meta-analysis that included 23 studies (6 studies with molecular characterization and 18 risk studies, of which 12 studies quantified risk for prostate cancer) reported an association of prostate cancer with Lynch syndrome.[84] In the six molecular studies included in the analysis, 73% (95% CI, 57%–85%) of prostate cancers in carriers of MMR gene pathogenic variants were MMR deficient. The RR of prostate cancer in carriers of MMR gene pathogenic variants was estimated to be 3.67 (95% CI, 2.32–6.67). Of the twelve risk studies, the RR of prostate cancer ranged from 2.11 to 2.28, compared with that seen in the general population depending on carrier status, prior diagnosis of colorectal cancer, or unknown male carrier status from families with a known pathogenic variant.

A study from three sites participating in the Colon Cancer Family Registry examined 32 cases of prostate cancer (mean age at diagnosis, 62 y; standard deviation, 8 y) in men with a documented MMR gene pathogenic variant (23 MSH2 carriers, 5 MLH1 carriers, and 4 MSH6 carriers).[85] Seventy-two percent (n = 23) had a previous diagnosis of colorectal cancer. Immunohistochemistry was used to assess MMR protein loss, which was observed in 22 tumors (69%); the pattern of loss of protein expression was 100% concordant with the germline pathogenic variant. The RR of prostate cancer was highest in carriers of MSH2 pathogenic variants (RR, 5.8; 95% CI, 2.6–20.9); the RRs in carriers of MLH1 and MSH6 pathogenic variants were 1.7 (95% CI, 1.1–6.7) and 1.3 (95% CI, 1.1–5.3), respectively. Gleason scores ranged from 5 to 10; two tumors had a Gleason score of 5; 22 tumors had a Gleason score of 6 or 7; and eight tumors had a Gleason score higher than 8. Sixty-seven percent (12 of 18) of the tumors were found to have perineural invasion, and 47% (9 of 19) had extracapsular invasion. A large observational cohort study, which included more than 6,000 MMR-variant carriers, reported an increased cumulative incidence of prostate cancer by age 70 years for specific MMR genes, as follows: MLH1 (7.0; 95% CI, 4.2–11.9), MSH2 (15.9; 95% CI, 11.2–22.5), and PMS2 (4.6; 95% CI, 0.8–67.5). No significant increase in prostate cancer incidence was reported for MSH6.[86]

Although the risk of prostate cancer appears to be elevated in families with Lynch syndrome, strategies for germline testing for MMR gene pathogenic variants in index prostate cancer patients remain to be determined.

A study of 1,133 primary prostate adenocarcinomas and 43 neuroendocrine prostate cancers (NEPC) conducted screening by MSH2 immunohistochemistry with confirmation by NGS.[87] MSI was assessed by polymerase chain reaction and NGS. Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other Gleason scores (P < .05). Three patients had germline variants in MSH2, of whom two had a primary Gleason score of 5. Pending further confirmation, these findings may support universal MMR screening of prostate cancer with a Gleason score of 9 to 10 to identify men who may be eligible for immunotherapy and germline testing.

ATM

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygous carriers of ATM pathogenic variants.[88] In the presence of DNA damage, the ATM protein is involved in mediating cell cycle arrest, DNA repair, and apoptosis.[89] Given evidence of other cancer risks in heterozygous ATM carriers, evidence of an association with prostate cancer susceptibility continues to emerge. A prospective case series of 10,317 Danish individuals who had a 36-year follow-up period, during which 2,056 individuals developed cancer, found that the ATM Ser49Cys variant was associated with increased prostate cancer risk (HR, 2.3; 95% CI, 1.1–5.0).[89] A retrospective case series of 692 men with metastatic prostate cancer, who were not selected based on a family history of cancer or the patient's age at cancer diagnosis, found that 1.6% of participants (11 of 692) had an ATM pathogenic variant.[9] Multiple independent reports have shown that the ATM P1054R variant, which is found in 2% of Europeans, is associated with increased prostate cancer risk.[13,90,91] For example, the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium found an OR of 1.16 (95% CI, 1.10–1.22) for the ATM P1054 variant's association with prostate cancer risk.[92] A subsequent PRACTICAL consortium study had 14 groups (five from North America, six from Europe, and two from Australia) and 8,913 participants (5,560 cases and 3,353 controls). Next-generation ATM sequencing data were standardized and ClinVar classifications were used to categorize the variants as Tier 1 (likely pathogenic) or Tier 2 (potentially deleterious). Prostate cancer risk in Tier 1 variants had an OR of 4.4 (95% CI, 2.0–9.5).[93]

CHEK2

CHEK2 has also been investigated for a potential association with prostate cancer risk. For more information on other cancers associated with CHEK2 pathogenic variants, see the CHEK2 section in Genetics of Breast and Gynecologic Cancers and the CHEK2 section in Genetics of Colorectal Cancer. A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found 1.9% (10 of 534 [men with data]) were found to have a CHEK2 pathogenic variant.[9] A systematic review and meta-analysis from eight retrospective cohort studies examining the relationship between CHEK2 variants (1100delC, IVS2+1G>A, I157T) and prostate cancer confirmed the association of the 1100delC (OR, 3.29; 95% CI, 1.85–5.85; P = .00) and I157T (OR, 1.80; 95% CI, 1.51–2.14; P = .00) variants with prostate cancer susceptibility.[94] A GWAS focusing on African American cases and controls identified a missense variant, I448S, which is associated with prostate cancer (risk allele frequency, 1.5%; OR, 1.62; 95% CI, 1.39–1.89, P = 7.50 × 10^-10).[95] Further studies of CHEK2 in large diverse populations are warranted.

TP53

TP53 has also been investigated for a potential association with prostate cancer risk. For more information about other cancers associated with TP53 pathogenic variants, see the Li-Fraumeni syndrome section in Genetics of Breast and Gynecologic Cancers. In a case series of 286 individuals from 107 families with a deleterious TP53 variant, 403 cancer diagnoses were reported, of which 211 were the first primary cancer including two prostate cancers diagnosed after age 45 years. Prostate cancer was also reported in 4 of 61 men with a second primary cancer.[96] In a Dutch case series of 180 families meeting either classic Li-Fraumeni syndrome (LFS) or Li-Fraumeni–like (LFL) family history criteria, a deleterious TP53 variant was identified in 24 families with one case of prostate cancer found in each group (LFS or LFL). Prostate cancer risks varied on the basis of the family history criteria with LFS (RR, 0.50; 95% CI, 0.01–3.00) and LFL (RR, 4.90; 95% CI, 0.10–27.00).[97] In a French case series of 415 families with a deleterious TP53 variant, four prostate cancers were reported, with a mean age at diagnosis of 63 years (range, 57–71 y).[98]

Germline TP53 pathogenic variants have also been identified in men with prostate cancer who have undergone tumor testing. A prospective case series of 42 men with either localized, biochemically recurrent, or metastatic prostate cancer unselected for cancer family history or age at diagnosis undergoing tumor-only somatic testing found that 2 of 42 men (5%) were found to have a suspected TP53 germline pathogenic variant.[99]

Further evidence supports an association between prostate cancer and germline TP53 pathogenic variants,[100,101,102] although additional studies to clarify the association with this gene are warranted.

NBN/NBS1

NBN, which is also known as NBS1, has been investigated for a potential association with risk of prostate cancer. A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found that 0.3% (2 of 692 men) had an NBN pathogenic variant.[9] A prospective cohort of men with prostate cancer diagnosed between 1999 and 2015 in Poland confirmed the association of the NBN 657del5 variant and prostate cancer (OR, 2.5; P < .001) and mortality (HR, 1.6; P = .001), which remained significant after adjusting for age at diagnosis, PSA, stage, and grade.[103] The risk of prostate cancer in NBN 657del5 carriers is influenced by the genotype at the E185Q polymorphism.

EPCAM

EPCAM testing has been included in some multigene panels likely due to EPCAM variants silencing MSH2. Specific large genomic rearrangement variants at the 3' end of EPCAM (which lies near the MSH2 gene) induce methylation of the MSH2 promoter, resulting in MSH2 protein loss.[104] Pathogenic variants in MSH2 are associated with Lynch syndrome and an increase in prostate cancer risk.[85] For more information on EPCAM and MSH2, see the Mismatch repair genes section or the Lynch Syndrome section in Genetics of Colorectal Cancer. Thus far, studies have not found an association between increased prostate cancer risk and EPCAM pathogenic variants.[9]

Germline Pathogenic Variants in Men With Metastatic Prostate Cancer

The metastatic prostate cancer setting is also contributing insights into the germline pathogenic variant spectrum of prostate cancer. Clinical sequencing of 150 metastatic tumors from men with castrate-resistant prostate cancer identified alterations in genes involved in DNA repair in 23% of men.[105] Interestingly, 8% of these variants were pathogenic and present in the germline. Another study focused on tumor-normal sequencing of advanced and metastatic cancers identified germline pathogenic variants in 19.6% of men (71 of 362) with prostate cancer.[106] Germline pathogenic variants were found in BRCA1, BRCA2, MSH2, MSH6, PALB2, PMS2, ATM, BRIP1, NBN, as well as other genes. These and other studies are summarized in Table 9. The contribution of germline variants identified from large sequencing efforts to inherited prostate cancer predisposition requires molecular confirmation of genes not classically linked to prostate cancer risk.

Table 9. Summary of Tumor Sequencing Studies With Germline Findings

Study	Cohort	Germline Results for Prostate Cancer		Comments
mCRPC = metastatic castration-resistant prostate cancer.
a Potential overlap of cohorts.
Robinson et al. (2015)a[105]	Whole-exomeand transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 men with mCRPC	8% had germline pathogenic variants:
		—BRCA2: 9/150 (6.0%)
		—ATM: 2/150 (1.3%)
		—BRCA1: 1/150 (0.7%)
Pritchard et al. (2016)a[9]	692 men with metastatic prostate cancer, unselected for family history; analysis focused on 20 genes involved in maintaining DNA integrity and associated withautosomal dominantcancer–predisposing syndromes	82/692 (11.8%) had germline pathogenic variants:		Frequency of germline pathogenic variants in DNA repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer in the Cancer Genome Atlas (P < .001)
		—BRCA2: 37/692 (5.3%)
		—ATM: 11/692 (1.6%)
		—BRCA1: 6/692 (0.9%)
Schrader et al. (2016)[107]	1,566 patients undergoing tumor profiling (341 genes) with matched normal DNA at a single institution; 97 cases of prostate cancer included	10/97 (10.3%) had germline pathogenic variants:
		—BRCA2: 6/97 (6.2%)
		—BRCA1: 1/97 (1.0%)
		—MSH6: 1/97 (1.0%)
		—MUTYH: 1/97 (1.0%)
		—PMS2: 1/97 (1.0%)

Genetic Testing for Prostate Cancer Precision Oncology

Targeted therapies on the basis of genetic results are increasingly driving options and strategies for treatment in oncology. These therapeutic approaches include candidacy for targeted therapy (such as poly [ADP-ribose] polymerase [PARP] inhibitors or immune checkpoint inhibitors), use of platinum-based chemotherapy, and sequencing of androgen-signaling therapy versus chemotherapy. Multiple genetically informed clinical trials are under way for men with prostate cancer.[108]Table 10 summarizes some of the published precision oncology and precision management studies.

Table 10. Summary of Precision Oncology or Precision Management Studies Involving Germline Pathogenic Variant Status

Study	Cohort	Germline Results	Intervention		Outcomes and Comments
ADT = androgen deprivation therapy; AR = androgen receptor; CI = confidence interval; CSS = cause-specific survival; DDR = DNA damage repair; FDA = U.S. Food and Drug Administration; HR = hazard ratio; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; mPC = metastatic prostate cancer; ORR = objective response rate; OS = overall survival; PARP = poly (ADP-ribose) polymerase; PC = prostate cancer; PFS = progression-free survival; PSA = prostate-specific antigen; RR = relative risk.
a This study reported both germline and somatic genetic test results.
Retrospective
Annala et al. (2017)[109]	319 men with mCRPC; performed germline sequencing of 22 DNA repair genes; all participants previously received ADT and their PCs progressed	24/319 (7.5%) had DDR germline pathogenic variants:	Patientswith mCRPC and a germline pathogenic variant received the following as a first-line AR-targeted therapy: docetaxel/cabazitaxel (41%), enzalutamide (23%), or abiraterone (36%)		Patients with DNA repair defects had decreased responses to ADT:
		—BRCA2: 16/319 (5.0%)
		—ATM: 1/319 (0.3%)			— Time from ADT initiation to mCRPC: Germline positive, 11.8 mo (n = 22) vs. germline negative, 19.0 mo (n = 113) (P = .031)
		—BRCA1: 1/319 (0.3%)	Patients with mCRPC butwithout a germline pathogenic variant received the following as a first-line AR-targeted therapy: docetaxel/cabazitaxel (33%), enzalutamide (18%), abiraterone (39%), or other (10%)
		—PALB2: 2/319 (0.6%)			— PFS on first-line AR-targeted therapy: Germline positive, 3.3 mo vs. germline negative, 6.2 mo (P = .01)
Pomerantz et al. (2017)[110]	141 men with mCRPC treated with docetaxel	8/141 (5.7%) hadBRCA2germline pathogenic variants	Patients received at least two doses of carboplatin and docetaxel		6/8 men withBRCA2germline pathogenic variants (75%) had PSA levels that declined by 50% vs. 23/133 in men withoutBRCA2germline pathogenic variants (17%) (P< .001)
					A small case series (n = 3) showed a response to platinum chemotherapy with biallelic inactivation ofBRCA2, defined as either biallelic somaticBRCA2pathogenic variants or a germline pathogenic variant plus a somaticBRCA2pathogenic variant[111]
Mateo et al. (2018)[112]	390 men with mPC; retrospective review	60/390 (15.4%) had DDR germline pathogenic variants:	Patients received abiraterone, enzalutamide, and docetaxel; an exploratory subgroup analysis was done for PARP inhibitors/platinum chemotherapy		Similar findings were observed for DDR pathogenic variant carriers and noncarriers for several outcome measures:
					— Median OS from castration resistance (3.2 y in carriers vs 3.0 y in noncarriers;P = .73)
					— Median docetaxel PFS (6.8 mo in carriers vs. 5.1 mo in noncarriers)
		—BRCA2: 37/390 (9.5%)			— RRs for PC (61% in carriers vs. 54% in noncarriers)
					— Median PFS on first-line abiraterone/enzalutamide (8.3 mo in both carriers and noncarriers)
					— RR of PC on first-line abiraterone/enzalutamide (46% in carriers vs. 56% in noncarriers)
Carter et al. (2019)[113]	1,211 men with PC on active surveillance	2.1% of patients had germline pathogenic variants inBRCA1/BRCA2/ATM	Patients were put on active surveillance		289 patients had their PC tumor grades reclassified: 11/26 patients had pathogenic variants inBRCA1/BRCA2/ATMand 278/1,185 patients did not have a pathogenic variant inBRCA1/BRCA2/ATM(noncarriers); adjusted HR, 1.96 (95% CI, 1.004–3.84;P = .04)
					Tumor reclassification occurred in 6/11BRCA2carriers and 283/1,200 noncarriers; adjusted HR, 2.74 (95% CI, 1.26–5.96;P = .01)
					Of the men who had their PCs reclassified, 3.8% had aBRCA1,BRCA2, orATMpathogenic variant, and 2.1% only had aBRCA2 pathogenic variant. Of the men whose PCs were not reclassified, 1.6% had aBRCA1,BRCA2, orATMpathogenic variant, and 0.5% only had aBRCA2 pathogenic variant. TheP value forBRCA1/BRCA2/ATMcarriers with PCs reclassified versus those without PCs reclassified was .04. TheP value forBRCA2carriers with PCs reclassified versus those without PCs reclassified was .03
Marshall et al. (2019)[114]	46 men with mCRPC were offered olaparib; 23 men had germline pathogenic variants (13 men were not tested)	23 men had germline pathogenic variants inBRCA1/BRCA2/ATM; 2 men hadBRCA1pathogenic variants, 15 men hadBRCA2 pathogenic variants, and 6 men hadATMpathogenic variants	Patients received olaparib		When patients were given olaparib, PSA levels were reduced by 50% in 13/17 (76%) men withBRCA1/BRCA2pathogenic variants and in 0/6 (0%) men withATMpathogenic variants (Fisher's exact test;P = .002)
					Patients withBRCA1/BRCA2 pathogenic variants had a median PFS of 12.3 mo, while patients withATMpathogenic variants had a median PFS of 2.4 mo (HR, 0.17; 95% CI, 0.05–0.57;P = .004)
Sokolova et al. (2021)[115]	90 men with PC; 76/90 had metastatic disease when their PC was diagnosed; participants were matched for PC stage and year of germline testing; participants had similar ages, Gleason grades, and PSA levels at diagnosis	45 men withATMgermline pathogenic variants; 45 men withBRCA2 germline pathogenic variants	Patients received various systemic therapies		No changes were observed when different groups were given abiraterone, enzalutamide, or docetaxel
					When patients were given PARP inhibitors, PSA levels were reduced by 50% in 0/7 men withATMgermline pathogenic variants and in 12/14 men withBRCA2germline pathogenic variants (P< .001); this response was significant
					Study limitations included the following: retrospective study, no zygosity data
Prospective
Antonarakis et al. (2018)[116]	172 men with mCRPC began treatment with abiraterone or enzalutamide	22/172 (12.8%) had DDR germline pathogenic variants:	Patients received first-line hormonal therapy (abiraterone or enzalutamide)		In propensity score–weighted multivariable analyses, outcomes were superior in men with germlineBRCA1/BRCA2/ATMvariants with respect to PSA-PFS (HR, 0.48; 95% CI, 0.25–0.92;P = .027), PFS (HR, 0.52; 95% CI, 0.28–0.98;P = .044), and OS (HR, 0.34; 95% CI, 0.12–0.99;P = .048). These results were not observed for men with non-BRCA1/BRCA2/ATMgermline variants (P> .10)
		—BRCA1/BRCA2/ATM: 9/172 (5.2%)			Study limitations included the following: only 9 patients withBRCA1/BRCA2/ATMpathogenic variants
Castro et al. (2019)[117]	419 men with mCRPC were enrolled when they were diagnosed with mPC	68/419 (16.2%) had DDR germline pathogenic variants:	Patients received an androgen-signaling inhibitor (abiraterone or enzalutamide) as a first-line therapy and a taxane (docetaxel was given in 96.3% of patients) as a second-line therapyor patients received a taxane as a first-line therapy and an androgen-signaling inhibitor (abiraterone or enzalutamide) as a second-line therapy		CSS betweenATM/BRCA1/BRCA2/PALB2carriers and noncarriers was not statistically significant (23.3 mo vs. 33.2 mo;P = .264)
		—BRCA2: 14/419 (3.3%)
		—ATM: 8/419 (1.9%)			CSS was halved inBRCA2carriers (17.4 mo vs. 33.2 mo;P = .027), andBRCA2pathogenic variants were identified as an independent prognostic factor for CSS (HR, 2.11;P = .033)
		—BRCA1: 4/419 (1%)			Significant interactions betweenBRCA2status and treatment type (androgen-signaling inhibitor vs. taxane therapy) were observed (CSS-adjustedP = .014; PFS-adjustedP = .005)
		—PALB2: None			CSS (24.0 mo vs. 17.0 mo) and PFS (18.9 mo vs. 8.6 mo) were greater inBRCA2carriers treated with first-line abiraterone or enzalutamide when compared with first-line taxanes
de Bono et al. (2020)[118]	387 men in the PROfound study who had mCRPC with disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone)	Currently, the FDA has approved olaparib for use in patients with mCRPC who have a somatic or germline pathogenic variant in an HRR gene. The PROfound study cited data fromMateo et al. 2015, which discovered that about half of the HRR gene variants in patient tumors were germline in nature. Results in this study reported on olaparib response in individuals with somatic variants. Data on germline pathogenic variants will be reported in the future	Randomized, open-label, phase III trial in which patients received olaparib (300 mg twice per day)or the physician's choice of enzalutamide (160 mg once per day) or abiraterone (1,000 mg once per day) plus prednisone (5 mg twice per day)		In cohort A, imaging-based PFS was significantly longer in the olaparib group than in the control group (median, 7.4 mo vs. 3.6 mo; HR for progression or death, 0.34; 95% CI, 0.25–0.47;P< .001). The median OS in cohort A was 18.5 mo in the olaparib group and 15.1 mo in the control group; 81% of the patients in the control group who had disease progression crossed over to receive olaparib
		Cohort A: 245 men with >1 somatic variant inBRCA1,BRCA2, orATM
		Cohort B: 142 men with >1 somatic variant in any of the following genes:BRIP1,BARD1,CDK12,CHEK1,CHEK2,FANCL,PALB2,PPP2R2A,RAD51B,RAD51C,RAD51D, orRAD54L
Hussain et al. (2020)[119]	387 men with mCRPC in the PROfound study; PC progressed when taking enzalutamide, abiraterone, or both	Currently, the FDA has approved olaparib for use in patients with mCRPC who have a somatic or germline pathogenic variant in an HRR gene. The PROfound study cited data fromMateo et al. 2015, which discovered that about half of the HRR gene variants in patient tumors were germline in nature. Results in this study reported on olaparib response in individuals with somatic variants. Data on germline pathogenic variants will be reported in the future	Patients received treatment that was randomly assigned in a 2:1 ratio for olaparib versus control therapy; control therapy consisted of the provider's choice of enzalutamide or abiraterone, plus prednisone. Crossover to olaparib was permitted when PC progressed on imaging		The median OS in cohort A was 19.1 mo with olaparib and 14.7 mo with control therapy. The HR for death (adjusted for crossover from control therapy) was 0.42 (95% CI, 0.19–0.91)
		Cohort A: 245 men with >1 somatic variant inBRCA1,BRCA2, orATM			The median OS in cohort B was 14.1 mo for olaparib and 11.5 mo for control therapy. The HR for death (adjusted for crossover from control therapy) was 0.83 (95% CI, 0.11–5.98)
		Cohort B: 142 men with >1 somatic variant in any of the following genes:BRIP1,BARD1,CDK12,CHEK1,CHEK2,FANCL,PALB2,PPP2R2A,RAD51B,RAD51C,RAD51D, orRAD54L
Abida et al. (2020)a[120]	115 men with mCRPC from the TRITON2 study with a deleterious somatic or germline pathogenic variant inBRCA1/BRCA2; patients had mCRPCs that progressed after treatment with one to two lines of next-generation AR-directed therapy and one taxane-based chemotherapy	44/115 (38%) hadBRCA1/BRCA2germline pathogenic variants:	Patients received one or more doses of rucaparib (600 mg)		The ORR was 43.5% in men with measurable disease and 50.8% in men without measurable disease. ORRs were similar for men with germline and somatic variants and for men withBRCA1/BRCA2pathogenic variants
		—BRCA1: 5/115 (4%)
		—BRCA2: 39/115 (34%)
		71/115 (62%) hadBRCA1/BRCA2somatic variants:			63/115 men had a confirmed PSA response (54.8%), which differed by gene; however, theBRCA1group was small:
		—BRCA1: 8/115 (7%)			— BRCA1: 2/13 (15.4%)
		—BRCA2: 63/115 (55%)			—BRCA2: 61/102 (59.8%)
De Bono et al. (2021)a[121]	104 men with progressive mCRPC and pathogenic variants in DDR-HRR genes; patients received at least one dose of talazoparib	25/71 (25%) patients had germline pathogenic variants: 13 inBRCA2, 4 inATM, and 8 in other genes	Patients received one or more doses of talazoparib per day (received 1 mg per day or 0.75 mg per day if the patient had moderate renal impairment)		The ORR was observed in 7/28 (25%) men with germline pathogenic variants
		Patients also had somatic variants in the following genes: 61 inBRCA1/2, 57 inBRCA2, 4 inPALB2, 17 inATM, 22 in other genes (ATR,CHEK2,FANCA,MLH1,MRE11A,NBN, andRAD51C)			After a median follow-up period of 16.4 mo (range, 11.1–22.1), the ORR for patients with somatic variants was 29.8% (31 of 104 patients; 95% CI, 21.2%–39.6%). Clinical benefit (defined as patients with complete response, partial response, or stable disease for ≥6 months from treatment start) varied between individuals with different pathogenic variants:BRCA1/2(56%),BRCA2(56%),PALB2(25%),ATM(24%), other (0%)

Genetic results are increasingly informing treatment and management strategies for prostate cancer. Confirmation of somatic mutations through germline testing is needed so that additional recommendations can be made regarding cancer risk for patients and families. For more information about available practice guidelines for prostate cancer genetic testing, see Table 2.

References:

1. Giri VN, Knudsen KE, Kelly WK, et al.: Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 36 (4): 414-424, 2018.
2. Gillessen S, Attard G, Beer TM, et al.: Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 73 (2): 178-211, 2018.
3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed March 1, 2023.
4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2022. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed March 17, 2023.
5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 1.2022. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed November 22, 2022.
6. Giri VN, Knudsen KE, Kelly WK, et al.: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol 38 (24): 2798-2811, 2020.
7. Raymond VM, Gray SW, Roychowdhury S, et al.: Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. J Natl Cancer Inst 108 (4): , 2016.
8. Gillessen S, Attard G, Beer TM, et al.: Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol 77 (4): 508-547, 2020.
9. Pritchard CC, Mateo J, Walsh MF, et al.: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375 (5): 443-53, 2016.
10. Giri VN, Hegarty SE, Hyatt C, et al.: Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing. Prostate 79 (4): 333-339, 2019.
11. Nicolosi P, Ledet E, Yang S, et al.: Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol 5 (4): 523-528, 2019.
12. Lang SH, Swift SL, White H, et al.: A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol 55 (3): 597-616, 2019.
13. Momozawa Y, Iwasaki Y, Hirata M, et al.: Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls. J Natl Cancer Inst 112 (4): 369-376, 2020.
14. Thompson D, Easton DF; Breast Cancer Linkage Consortium: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002.
15. Liede A, Karlan BY, Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 (4): 735-42, 2004.
16. Mersch J, Jackson MA, Park M, et al.: Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121 (2): 269-75, 2015.
17. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.
18. Thompson D, Easton D; Breast Cancer Linkage Consortium: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68 (2): 410-9, 2001.
19. Silvestri V, Leslie G, Barnes DR, et al.: Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). JAMA Oncol 6 (8): 1218-1230, 2020.
20. Li S, Silvestri V, Leslie G, et al.: Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. J Clin Oncol 40 (14): 1529-1541, 2022.
21. Ostrander EA, Udler MS: The role of the BRCA2 gene in susceptibility to prostate cancer revisited. Cancer Epidemiol Biomarkers Prev 17 (8): 1843-8, 2008.
22. Oh M, Alkhushaym N, Fallatah S, et al.: The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis. Prostate 79 (8): 880-895, 2019.
23. Nastiuk KL, Mansukhani M, Terry MB, et al.: Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40 (3): 172-7, 1999.
24. Vazina A, Baniel J, Yaacobi Y, et al.: The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 83 (4): 463-6, 2000.
25. Lehrer S, Fodor F, Stock RG, et al.: Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 78 (6): 771-3, 1998.
26. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.
27. Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996.
28. Roa BB, Boyd AA, Volcik K, et al.: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14 (2): 185-7, 1996.
29. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.
30. Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003.
31. Kirchhoff T, Kauff ND, Mitra N, et al.: BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 10 (9): 2918-21, 2004.
32. Agalliu I, Gern R, Leanza S, et al.: Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res 15 (3): 1112-20, 2009.
33. Gallagher DJ, Gaudet MM, Pal P, et al.: Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 16 (7): 2115-21, 2010.
34. Johannesdottir G, Gudmundsson J, Bergthorsson JT, et al.: High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res 56 (16): 3663-5, 1996.
35. Eerola H, Pukkala E, Pyrhönen S, et al.: Risk of cancer in BRCA1 and BRCA2 mutation-positive and -negative breast cancer families (Finland). Cancer Causes Control 12 (8): 739-46, 2001.
36. Cybulski C, Wokołorczyk D, Kluźniak W, et al.: An inherited NBN mutation is associated with poor prognosis prostate cancer. Br J Cancer 108 (2): 461-8, 2013.
37. Cybulski C, Górski B, Gronwald J, et al.: BRCA1 mutations and prostate cancer in Poland. Eur J Cancer Prev 17 (1): 62-6, 2008.
38. Agalliu I, Karlins E, Kwon EM, et al.: Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer 97 (6): 826-31, 2007.
39. Agalliu I, Kwon EM, Zadory D, et al.: Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer. Clin Cancer Res 13 (3): 839-43, 2007.
40. Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.: Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99 (12): 929-35, 2007.
41. Kote-Jarai Z, Leongamornlert D, Saunders E, et al.: BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer 105 (8): 1230-4, 2011.
42. Leongamornlert D, Mahmud N, Tymrakiewicz M, et al.: Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer 106 (10): 1697-701, 2012.
43. Nyberg T, Frost D, Barrowdale D, et al.: Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study. Eur Urol 77 (1): 24-35, 2020.
44. Edwards SM, Evans DG, Hope Q, et al.: Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 103 (6): 918-24, 2010.
45. Thorne H, Willems AJ, Niedermayr E, et al.: Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res (Phila) 4 (7): 1002-10, 2011.
46. Castro E, Goh C, Olmos D, et al.: Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 31 (14): 1748-57, 2013.
47. Akbari MR, Wallis CJ, Toi A, et al.: The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer. Br J Cancer 111 (6): 1238-40, 2014.
48. Taylor RA, Fraser M, Livingstone J, et al.: Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nat Commun 8: 13671, 2017.
49. Narod SA, Neuhausen S, Vichodez G, et al.: Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 99 (2): 371-4, 2008.
50. Castro E, Goh C, Leongamornlert D, et al.: Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur Urol 68 (2): 186-93, 2015.
51. Lange EM, Gillanders EM, Davis CC, et al.: Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1. Prostate 57 (4): 326-34, 2003.
52. Zuhlke KA, Madeoy JJ, Beebe-Dimmer J, et al.: Truncating BRCA1 mutations are uncommon in a cohort of hereditary prostate cancer families with evidence of linkage to 17q markers. Clin Cancer Res 10 (18 Pt 1): 5975-80, 2004.
53. Douglas JA, Levin AM, Zuhlke KA, et al.: Common variation in the BRCA1 gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (7): 1510-6, 2007.
54. Lange EM, Robbins CM, Gillanders EM, et al.: Fine-mapping the putative chromosome 17q21-22 prostate cancer susceptibility gene to a 10 cM region based on linkage analysis. Hum Genet 121 (1): 49-55, 2007.
55. Ewing CM, Ray AM, Lange EM, et al.: Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 366 (2): 141-9, 2012.
56. Xu J, Lange EM, Lu L, et al.: HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet 132 (1): 5-14, 2013.
57. Chen Z, Greenwood C, Isaacs WB, et al.: The G84E mutation of HOXB13 is associated with increased risk for prostate cancer: results from the REDUCE trial. Carcinogenesis 34 (6): 1260-4, 2013.
58. Shang Z, Zhu S, Zhang H, et al.: Germline homeobox B13 (HOXB13) G84E mutation and prostate cancer risk in European descendants: a meta-analysis of 24,213 cases and 73, 631 controls. Eur Urol 64 (1): 173-6, 2013.
59. Handorf E, Crumpler N, Gross L, et al.: Prevalence of the HOXB13 G84E mutation among unaffected men with a family history of prostate cancer. J Genet Couns 23 (3): 371-6, 2014.
60. Laitinen VH, Wahlfors T, Saaristo L, et al.: HOXB13 G84E mutation in Finland: population-based analysis of prostate, breast, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 22 (3): 452-60, 2013.
61. Witte JS, Mefford J, Plummer SJ, et al.: HOXB13 mutation and prostate cancer: studies of siblings and aggressive disease. Cancer Epidemiol Biomarkers Prev 22 (4): 675-80, 2013.
62. Beebe-Dimmer JL, Hathcock M, Yee C, et al.: The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies. Cancer Epidemiol Biomarkers Prev 24 (9): 1366-72, 2015.
63. Gudmundsson J, Sulem P, Gudbjartsson DF, et al.: A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44 (12): 1326-9, 2012.
64. Huang H, Cai B: G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis. Tumour Biol 35 (2): 1177-82, 2014.
65. Cai Q, Wang X, Li X, et al.: Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget 6 (39): 42312-21, 2015.
66. Stott-Miller M, Karyadi DM, Smith T, et al.: HOXB13 mutations in a population-based, case-control study of prostate cancer. Prostate 73 (6): 634-41, 2013.
67. Alanee S, Shah S, Vijai J, et al.: Prevalence of HOXB13 mutation in a population of Ashkenazi Jewish men treated for prostate cancer. Fam Cancer 12 (4): 597-600, 2013.
68. Kote-Jarai Z, Mikropoulos C, Leongamornlert DA, et al.: Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann Oncol 26 (4): 756-61, 2015.
69. Sipeky C, Gao P, Zhang Q, et al.: Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer. Clin Cancer Res 24 (24): 6265-6276, 2018.
70. Lin X, Qu L, Chen Z, et al.: A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men. Prostate 73 (2): 169-75, 2013.
71. Marlin R, Créoff M, Merle S, et al.: Mutation HOXB13 c.853delT in Martinican prostate cancer patients. Prostate 80 (6): 463-470, 2020.
72. Na R, Wei J, Sample CJ, et al.: The HOXB13 variant X285K is associated with clinical significance and early age at diagnosis in African American prostate cancer patients. Br J Cancer 126 (5): 791-796, 2022.
73. Darst BF, Hughley R, Pfennig A, et al.: A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry. Eur Urol 81 (5): 458-462, 2022.
74. Karlsson R, Aly M, Clements M, et al.: A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk. Eur Urol 65 (1): 169-76, 2014.
75. MacInnis RJ, Severi G, Baglietto L, et al.: Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E. PLoS One 8 (2): e54727, 2013.
76. Nyberg T, Govindasami K, Leslie G, et al.: Homeobox B13 G84E Mutation and Prostate Cancer Risk. Eur Urol 75 (5): 834-845, 2019.
77. Soravia C, van der Klift H, Bründler MA, et al.: Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum. Am J Med Genet 121A (2): 159-62, 2003.
78. Haraldsdottir S, Hampel H, Wei L, et al.: Prostate cancer incidence in males with Lynch syndrome. Genet Med 16 (7): 553-7, 2014.
79. Grindedal EM, Møller P, Eeles R, et al.: Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev 18 (9): 2460-7, 2009.
80. Langeberg WJ, Kwon EM, Koopmeiners JS, et al.: Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes. Cancer Epidemiol Biomarkers Prev 19 (1): 258-64, 2010.
81. Bauer CM, Ray AM, Halstead-Nussloch BA, et al.: Hereditary prostate cancer as a feature of Lynch syndrome. Fam Cancer 10 (1): 37-42, 2011.
82. Dominguez-Valentin M, Joost P, Therkildsen C, et al.: Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. BMC Urol 16: 15, 2016.
83. Raymond VM, Mukherjee B, Wang F, et al.: Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 31 (14): 1713-8, 2013.
84. Ryan S, Jenkins MA, Win AK: Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 23 (3): 437-49, 2014.
85. Rosty C, Walsh MD, Lindor NM, et al.: High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer 13 (4): 573-82, 2014.
86. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al.: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22 (1): 15-25, 2020.
87. Guedes LB, Antonarakis ES, Schweizer MT, et al.: MSH2 Loss in Primary Prostate Cancer. Clin Cancer Res 23 (22): 6863-6874, 2017.
88. Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995.
89. Dombernowsky SL, Weischer M, Allin KH, et al.: Risk of cancer by ATM missense mutations in the general population. J Clin Oncol 26 (18): 3057-62, 2008.
90. Angèle S, Falconer A, Edwards SM, et al.: ATM polymorphisms as risk factors for prostate cancer development. Br J Cancer 91 (4): 783-7, 2004.
91. Meyer A, Wilhelm B, Dörk T, et al.: ATM missense variant P1054R predisposes to prostate cancer. Radiother Oncol 83 (3): 283-8, 2007.
92. Schumacher FR, Al Olama AA, Berndt SI, et al.: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat Genet 50 (7): 928-936, 2018.
93. Karlsson Q, Brook MN, Dadaev T, et al.: Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. Eur Urol Oncol 4 (4): 570-579, 2021.
94. Wang Y, Dai B, Ye D: CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med 8 (9): 15708-15, 2015.
95. Conti DV, Wang K, Sheng X, et al.: Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. J Natl Cancer Inst 109 (8): , 2017.
96. Mai PL, Best AF, Peters JA, et al.: Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 122 (23): 3673-3681, 2016.
97. Ruijs MW, Verhoef S, Rookus MA, et al.: TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet 47 (6): 421-8, 2010.
98. Bougeard G, Renaux-Petel M, Flaman JM, et al.: Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol 33 (21): 2345-52, 2015.
99. Cheng HH, Klemfuss N, Montgomery B, et al.: A Pilot Study of Clinical Targeted Next Generation Sequencing for Prostate Cancer: Consequences for Treatment and Genetic Counseling. Prostate 76 (14): 1303-11, 2016.
100. Stacey SN, Sulem P, Jonasdottir A, et al.: A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 43 (11): 1098-103, 2011.
101. Mittal RD, George GP, Mishra J, et al.: Role of functional polymorphisms of P53 and P73 genes with the risk of prostate cancer in a case-control study from Northern India. Arch Med Res 42 (2): 122-7, 2011.
102. Xu B, Xu Z, Cheng G, et al.: Association between polymorphisms of TP53 and MDM2 and prostate cancer risk in southern Chinese. Cancer Genet Cytogenet 202 (2): 76-81, 2010.
103. Rusak B, Kluźniak W, Wokołorczykv D, et al.: Inherited NBN Mutations and Prostate Cancer Risk and Survival. Cancer Res Treat 51 (3): 1180-1187, 2019.
104. Kovacs ME, Papp J, Szentirmay Z, et al.: Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 30 (2): 197-203, 2009.
105. Robinson D, Van Allen EM, Wu YM, et al.: Integrative clinical genomics of advanced prostate cancer. Cell 161 (5): 1215-28, 2015.
106. Mandelker D, Zhang L, Kemel Y, et al.: Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA 318 (9): 825-835, 2017.
107. Schrader KA, Cheng DT, Joseph V, et al.: Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol 2 (1): 104-11, 2016.
108. Carlo MI, Giri VN, Paller CJ, et al.: Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium. JCO Precis Oncol 2018: , 2018.
109. Annala M, Struss WJ, Warner EW, et al.: Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. Eur Urol 72 (1): 34-42, 2017.
110. Pomerantz MM, Spisák S, Jia L, et al.: The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 123 (18): 3532-3539, 2017.
111. Cheng HH, Pritchard CC, Boyd T, et al.: Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol 69 (6): 992-5, 2016.
112. Mateo J, Cheng HH, Beltran H, et al.: Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study. Eur Urol 73 (5): 687-693, 2018.
113. Carter HB, Helfand B, Mamawala M, et al.: Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. Eur Urol 75 (5): 743-749, 2019.
114. Marshall CH, Sokolova AO, McNatty AL, et al.: Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations. Eur Urol 76 (4): 452-458, 2019.
115. Sokolova AO, Marshall CH, Lozano R, et al.: Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations. Prostate 81 (16): 1382-1389, 2021.
116. Antonarakis ES, Lu C, Luber B, et al.: Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol 74 (2): 218-225, 2018.
117. Castro E, Romero-Laorden N, Del Pozo A, et al.: PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 37 (6): 490-503, 2019.
118. de Bono J, Mateo J, Fizazi K, et al.: Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 382 (22): 2091-2102, 2020.
119. Hussain M, Mateo J, Fizazi K, et al.: Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 383 (24): 2345-2357, 2020.
120. Abida W, Patnaik A, Campbell D, et al.: Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 38 (32): 3763-3772, 2020.
121. de Bono JS, Mehra N, Scagliotti GV, et al.: Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol 22 (9): 1250-1264, 2021.

Screening and Prevention Interventions in Familial Prostate Cancer

Background

Decisions about risk-reducing interventions for patients with an inherited predisposition to prostate cancer, as with any disease, are best guided by randomized controlled clinical trials and knowledge of the underlying natural history of the process. However, existing studies of screening for prostate cancer in high-risk men (men with a positive family history of prostate cancer and African American men) are predominantly based on retrospective case series or retrospective cohort analyses. Because awareness of a positive family history can lead to more frequent workups for cancer and result in apparently earlier prostate cancer detection, assessments of disease progression rates and survival after diagnosis are subject to selection, lead time, and length biases. This section focuses on screening and risk reduction of prostate cancer among men predisposed to the disease; data relevant to screening in high-risk men are primarily extracted from studies performed in the general population.

Screening

Information is limited about the efficacy of commonly available screening tests such as the digital rectal exam (DRE) and serum prostate-specific antigen (PSA) in men genetically predisposed to developing prostate cancer. Furthermore, comparing the results of studies that have examined the efficacy of screening for prostate cancer is difficult because studies vary with regard to the cutoff values chosen for an elevated PSA test. For a given sensitivity and specificity of a screening test, the positive predictive value (PPV) increases as the underlying prevalence of disease rises. Therefore, it is theoretically possible that the PPV and diagnostic yield will be higher for the DRE and for PSA in men with a genetic predisposition than in average-risk populations.[1,2]

Most retrospective analyses of prostate cancer screening cohorts have reported PPV for PSA, with or without DRE, among high-risk men in the range of 23% to 75%.[2,3,4,5,6] Screening strategies (frequency of PSA measurements or inclusion of DRE) and PSA cutoff for biopsy varied among these studies, which may have influenced this range of PPV. Cancer detection rates among high-risk men have been reported to be in the range of 4.75% to 22%.[2,5,6] Most cancers detected were of intermediate Gleason score (5–7), with Gleason scores of 8 or higher being detected in some high-risk men. Overall, there is limited information about the net benefits and harms of screening men at higher risk of prostate cancer. In addition, there is little evidence to support specific screening approaches in prostate cancer families at high risk. Risks and benefits of routine screening in the general population are discussed in Prostate Cancer Screening. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. A summary of prostate cancer screening recommendations for high-risk men by professional organizations is shown in Table 11 and Table 12.

Table 11. Available Recommendations for Prostate Cancer Screening inBRCA1,BRCA2, andHOXB13Carriers

​	Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2020)[7]	Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2023)[8]	NCCN Prostate Cancer Early Detection (Version 1.2022)a[9]
NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.
a Forgermline pathogenic variantsother thanBRCA2(includingATMand Lynch syndromegenes), it is reasonable to consider beginning shared decision-making about PSA screening at age 40 years and to consider screening at annual intervals, rather than every other year.
Screening in BRCA1Carriers	Consider baseline PSA for age >40 y or 10 years before the earliest prostate cancer diagnosis in the family	Consider prostate cancer screening starting at age 40 y	Consider beginning shared decision-making about PSA screening at age 40 y
		NCCN Genetic/Familial High-Risk Assessment guidelines suggest that individuals see the NCCN Prostate Cancer Early Detection guidelines for guidance on prostate cancer screening intervals[9]	Consider annual screening rather than screening every other year
Screening in BRCA2 Carriers	Recommend baseline PSA for age >40 y or 10 years before the earliest prostate cancer diagnosis in the family	Recommend prostate cancer screening starting at age 40 y	Recommend PSA screening starting at age 40 y
	Screening interval determined by baseline PSA level	NCCN Genetic/Familial High-Risk Assessment guidelines suggest that individuals see the NCCN Prostate Cancer Early Detection guidelines for guidance on prostate cancer screening intervals[9]	Consider annual screening rather than screening every other year
Screening in HOXB13 Carriers	Baseline PSA for age >40 y or 10 years before the earliest prostate cancer diagnosis in the family	None provided; there is insufficient evidence to make recommendations for prostate cancer management	Consider beginning shared decision-making about PSA screening at age 40 y
	Screening interval determined by baseline PSA level		Consider annual screening rather than screening every other year

Table 12. Summary of Prostate Cancer Screening Recommendations for Men Based on Family History, Race, and Ethnicity

Screening Recommendation Source	Population	Test	Age Screening Initiated	Frequency	Comments
DRE = digital rectal exam; FDR = first-degree relative; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen; SDR =second-degree relative.
a DRE is recommended in addition to PSA test for men with hypogonadism.
b A suspicious family history includes, but is not limited to, an FDR or SDR with metastatic prostate cancer, ovarian cancer, male breast cancer, female breast cancer at age ≤45 y, colorectal or endometrial cancer at age ≤50 y, or pancreatic cancer; this may also include two or more FDRs or SDRs with breast, prostate (excluding clinically localized Grade Group 1 disease), colorectal, or endometrial cancer at any age.
United States Preventive Services Task Force (2018)[10]	Men aged 55–69 y	PSA	N/A	N/A	In determining whether PSA-based screening is appropriate in individual cases, patients and clinicians should consider the benefits and harms of PSA screening based on family history, race and ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs
American College of Physicians (2013)[11]	African American men and men with anFDRdiagnosed with prostate cancer, especially at <65 y	PSA	≥45 y	No clear evidence to establish screening frequency	Counseling includes information about the uncertainties, risks, and potential benefits associated with prostate cancer screening
				No clear evidence to perform PSA test more frequently than every 4 y
	Men with multiple family members who were diagnosed with prostate cancer at <65 y	PSA	≥40 y
				PSA level >2.5 µg/L may warrant annual screening
American Urological Association (2013)[12]	African American men and men with a strong family history of prostate cancer	PSA	>40 to <55 y	Screening is individualized based on the patient's personal preferences and an informed discussion regarding the uncertainty of benefit and associated harms
American Cancer Society (2019)[13]	African American men	PSA with or without DREa	≥45 y	Screen every 1–2 y if PSA is <2.5 ng/mL; screen annually if PSA level is ≥2.5 ng/mL; if PSA levels are between 2.5–4.0 ng/mL, an individualized risk assessment can be performed, which incorporates other prostate cancer risk factors (particularly for high-grade cancer, which may be used for a referral recommendation)	Counseling consists of a review of the benefits and limitations of testing so that a clinician-assisted, informed decision about testing can be made. It is recommended that prostate cancer screening be accompanied by an informed decision-making process
	Men with an FDR who was diagnosed with prostate cancer at <65 y	PSA with or without DREa	≥45 y
	Men with multiple family members who were diagnosed with prostate cancer at <65 y	PSA with or without DREa	≥40 y
NCCN Prostate Cancer Early Detection (Version 1.2022)[9]	African American men	Baseline PSA; strongly consider baseline DRE	40–75 y	Consider screening at annual intervals rather than every other year	The panel states that it is reasonable for African American men to consider beginning shared decision-making about PSA screening with their providers at age 40 y
	Men with a suspicious family historyb	Baseline PSA; strongly consider baseline DRE	40–75 y	Screen every 2–4 y if PSA level <1 ng/mL, DRE normal	Referral to a cancer genetics professional is recommended for those with a known or suspected pathogenic variant in a cancersusceptibility gene [9]
				Screen every 1–2 y if PSA level 1–3 ng/mL, DRE normal (if done)

Level of evidence: 5

Screening in carriers ofBRCApathogenic variants

IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer) is an international study focused on prostate cancer screening in carriers of BRCA1/BRCA2 pathogenic variants versus noncarriers.[14] The study recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 noncarriers; 731 BRCA2 carriers, 428 BRCA2 noncarriers). A total of 199 men (8%) presented with PSA levels higher than 3.0 ng/mL, which was the study PSA cutoff for recommending a biopsy. The overall cancer detection rate was 36.4% (59 prostate cancers diagnosed among 162 biopsies). Prostate cancer by BRCA pathogenic variant status was as follows: BRCA1 carriers (n = 18), BRCA1 noncarriers (n = 10); BRCA2 carriers (n = 24), BRCA2 noncarriers (n = 7). Using published stage and grade criteria for risk classification,[15] intermediate- or high-risk tumors were diagnosed in 11 of 18 BRCA1 carriers (61%), 8 of 10 BRCA1 noncarriers (80%), 17 of 24 BRCA2 carriers (71%), and 3 of 7 BRCA2 noncarriers (43%). The PPV of PSA with a biopsy threshold of 3.0 ng/mL was 48% in carriers of BRCA2 pathogenic variants, 33.3% in BRCA2 noncarriers, 37.5% in BRCA1 carriers, and 23.3% in BRCA1 noncarriers. Ninety-five percent of the men were White; therefore, the results cannot be generalized to all ethnic groups.

Interim results from the IMPACT study (now comprising 2,932 participants including 919 BRCA1 carriers and 902 BRCA2 carriers) demonstrated a cancer incidence rate (per 1,000 person-years) that was higher in BRCA2 carriers compared with noncarriers (19 vs. 12; P = .03). There was no statistical difference in the cancer incidence rates between BRCA1 carriers and noncarriers. Cancer in BRCA2 carriers, but not in BRCA1 carriers, was diagnosed at an earlier age and was more likely to be clinically significant.[16]

Level of evidence (screening in carriers of BRCA pathogenic variants): 3

Chemoprevention of Prostate Cancer With Finasteride and Dutasteride

The benefits, harms, and supporting data regarding the use of finasteride and dutasteride for the prevention of prostate cancer in the general population are discussed in Prostate Cancer Prevention.

References:

1. Sartor O: Early detection of prostate cancer in African-American men with an increased familial risk of disease. J La State Med Soc 148 (4): 179-85, 1996.
2. Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999.
3. Catalona WJ, Antenor JA, Roehl KA, et al.: Screening for prostate cancer in high risk populations. J Urol 168 (5): 1980-3; discussion 1983-4, 2002.
4. Valeri A, Cormier L, Moineau MP, et al.: Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 168 (2): 483-7, 2002.
5. Narod SA, Dupont A, Cusan L, et al.: The impact of family history on early detection of prostate cancer. Nat Med 1 (2): 99-101, 1995.
6. Giri VN, Beebe-Dimmer J, Buyyounouski M, et al.: Prostate cancer risk assessment program: a 10-year update of cancer detection. J Urol 178 (5): 1920-4; discussion 1924, 2007.
7. Giri VN, Knudsen KE, Kelly WK, et al.: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol 38 (24): 2798-2811, 2020.
8. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed March 1, 2023.
9. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 1.2022. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed November 22, 2022.
10. U.S. Preventative Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Rockville, Md: U.S. Preventative Services Task Force, 2018. Available online. Last accessed November 22, 2022.
11. Qaseem A, Barry MJ, Denberg TD, et al.: Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 158 (10): 761-9, 2013.
12. Carter HB, Albertsen PC, Barry MJ, et al.: Early detection of prostate cancer: AUA Guideline. J Urol 190 (2): 419-26, 2013.
13. American Cancer Society: Cancer screening in the United States, 2019: a review of current American Cancer Society guidelines and current issues in cancer screening. American Cancer Society, 2019. Available online. Last accessed November 22, 2022.
14. Bancroft EK, Page EC, Castro E, et al.: Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur Urol 66 (3): 489-99, 2014.
15. National Collaborating Centre for Cancer (UK): Prostate Cancer: Diagnosis and Treatment. Cardiff, UK: National Collaborating Centre for Cancer, 2008. Available online. Last accessed November 22, 2022.
16. Page EC, Bancroft EK, Brook MN, et al.: Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. Eur Urol 76 (6): 831-842, 2019.

Prostate Cancer Risk Assessment

This section describes current approaches of assessing and counseling patients about prostate cancer susceptibility. Genetic counseling for men at increased risk of prostate cancer encompasses all of the elements of genetic counseling for other hereditary cancers. For more information, see Cancer Genetics Risk Assessment and Counseling. The components of genetic counseling include concepts of prostate cancer risk, reinforcing the importance of detailed family history, pedigree analysis to derive age-related risk, and offering participation in research studies to those individuals who have multiple affected family members.[1,2] Families with prostate cancer can be referred to ongoing research studies; however, these studies will not provide individual genetic results to participants.

Prostate cancer will affect an estimated one in eight American men during their lifetimes.[3] Evidence exists to support the hypothesis that approximately 5% to 10% of all prostate cancer is due to rare autosomal dominant prostate cancer susceptibility genes.[4,5] The proportion of prostate cancer associated with an inherited susceptibility may be even larger.[6,7,8] Men are generally considered to be candidates for genetic counseling regarding prostate cancer risk if they have a family history of prostate cancer. The Hopkins Criteria provide a working definition of hereditary prostate cancer families.[9] The three criteria include the following:

1. Three or more first-degree relatives (father, brother, son), or
2. Three successive generations of either the maternal or paternal lineages, or
3. At least two relatives affected at or before age 55 years.

Families need to fulfill only one of these criteria to be considered to have hereditary prostate cancer. One study investigated attitudes regarding prostate cancer susceptibility among sons of men with prostate cancer.[10] They found that 90% of sons were interested in knowing whether there is an inherited susceptibility to prostate cancer and would be likely to undergo screening and consider genetic testing if there was a family history of prostate cancer; however, similar high levels of interest in genetic testing for other hereditary cancer syndromes have not generally been borne out in testing uptake once the clinical genetic test becomes available.

Risk Assessment and Analysis

Assessment of a man concerned about his inherited risk of prostate cancer should include taking a detailed family history; eliciting information regarding personal prostate cancer risk factors such as age, race, and dietary intake of fats and dairy products; documenting other medical problems; and evaluating genetics-related psychosocial issues.

Family history documentation is based on construction of a pedigree, and generally includes the following:

• The history of cancer in both maternal and paternal bloodlines.
• All primary cancer diagnoses (not just prostate cancer) and ages at diagnosis.
• Race and ethnicity.
• Other health problems including benign prostatic hypertrophy.[11]

For more information, see the Documenting the family history section in Cancer Genetics Risk Assessment and Counseling.

Analysis of the family history generally consists of four components:

1. Evaluation of the pattern of cancers in the family to identify cancer clusters, which might suggest a known inherited cancer syndrome. In addition to site-specific prostate cancer, other cancer susceptibility syndromes include prostate cancer as a component tumor (e.g., hereditary breast/ovarian cancer syndrome [associated with pathogenic variants in BRCA1 and BRCA2]).
2. Assessment for genetic transmission. The pedigree should be assessed for evidence of both autosomal dominant and X-linked inheritance, which may be associated with a higher likelihood of having a hereditary prostate cancer syndrome. Autosomal dominant transmission is characterized by the presence of affected family members in sequential generations, with approximately 50% of males in each generation affected with prostate cancer. X-linked inheritance is suggested by apparent transmission of susceptibility from affected males in the maternal lineage. For more information, see the Analysis of the family history section in Cancer Genetics Risk Assessment and Counseling.
3. Age of prostate cancer diagnoses in the family. An inherited susceptibility to prostate cancer may be likely in families with early-onset prostate cancer.[12] However, genetic research is also under way in families with an older age of prostate cancer onset. In the aggregate, the data are inconsistent relative to whether hereditary prostate cancer is routinely characterized by a younger-than-usual age at diagnosis.
4. Risk assessment based on family and epidemiological studies. Multiple studies have reported that first-degree relatives of men affected with prostate cancer are two to three times more likely to develop prostate cancer than men in the general population. In some studies, the relative risk (RR) of prostate cancer is highest among families who develop prostate cancer at an earlier age, consistent with other cancer susceptibility syndromes in which early age at onset is a common feature. It has been estimated that male relatives of men diagnosed with prostate cancer younger than 53 years have a 40% lifetime cumulative risk of developing prostate cancer.[13] A population-based case-control study of more than 1,500 cases and 1,600 controls, in which White, African American, and Asian American individuals were studied, reported an odds ratio of 2.5 for men with an affected first-degree relative after adjusting for age and ethnicity.[14] For men with a brother and father or son affected with prostate cancer, the RR was estimated to be 6.4.

A number of studies have examined the accuracy of the family history of prostate cancer provided by men with prostate cancer. This has clinical importance when risk assessments are based on unverified family history information. In an Australian study of 154 unaffected men with a family history of prostate cancer, self-reported family history was verified from cancer registry data in 89.6% of cases.[15] Accuracy of age at diagnosis within a 3-year range was correct in 83% of the cases, and accuracy of age at diagnosis within a 5-year range was correct in 93% of the cases. Self-reported family history from men younger than 55 years and reports about first-degree relatives had the highest degree of accuracy.[15] Self-reported family history of prostate cancer, however, may not be reliably reported over time,[16] which underscores the need to verify objectively reported prostate cancer diagnoses when trying to determine whether a patient has a significant family history.

The personal health and risk-factor history includes, but is not limited to, the following:

• Family history.
• Age.
• Race.
• Current and past diet history, including fat intake.
• Current and past use of drugs that can affect prostatic growth, such as steroids (e.g., finasteride [Proscar]). For more information on finasteride and prostate cancer, see Prostate Cancer Prevention.
• Current and past use of complementary and alternative medications (e.g., saw palmetto, PC-SPES).[17] For more information, see PC-SPES.

The most definitive risk factors for prostate cancer are age, race, and family history.[18] The correlation between other risk factors and prostate cancer risk is not clearly established. Despite this limitation, cancer risk counseling is an educational process that provides details about prostate cancer risk factors. The discussion regarding these other risk factors should be individualized to incorporate the patient's personal health and risk factor history. For more information, see the Risk Factors for Prostate Cancer section.

The psychosocial assessment in this context might include evaluation of the following:

• Level of psychological distress.
• Perceived risk of prostate cancer.
• Past history of depression, anxiety, or other mental illness.

One study found that psychological distress was greater among men attending prostate cancer screening who had a family history of the disease, particularly if they also reported an overestimation of prostate cancer risk. Psychological distress and elevated risk perception may influence adherence to cancer screening and risk management strategies. Consultation with a mental health professional may be valuable if serious psychosocial issues are identified.[19]

Genetic Testing

Multigene (panel) tests for variants in genes associated with prostate cancer susceptibility are currently available and are increasingly being used in the clinic. For more information, see the Multigene (Panel) Testing in Prostate Cancer section.

References:

1. Nieder AM, Taneja SS, Zeegers MP, et al.: Genetic counseling for prostate cancer risk. Clin Genet 63 (3): 169-76, 2003.
2. Bruner DW, Baffoe-Bonnie A, Miller S, et al.: Prostate cancer risk assessment program. A model for the early detection of prostate cancer. Oncology (Huntingt) 13 (3): 325-34; discussion 337-9, 343-4 pas, 1999.
3. American Cancer Society: Cancer Facts and Figures 2022. American Cancer Society, 2022. Available online. Last accessed October 7, 2022.
4. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990.
5. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.
6. Lesko SM, Rosenberg L, Shapiro S: Family history and prostate cancer risk. Am J Epidemiol 144 (11): 1041-7, 1996.
7. Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997.
8. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998.
9. Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.
10. Bratt O, Kristoffersson U, Lundgren R, et al.: Sons of men with prostate cancer: their attitudes regarding possible inheritance of prostate cancer, screening, and genetic testing. Urology 50 (3): 360-5, 1997.
11. Pienta KJ, Esper PS: Risk factors for prostate cancer. Ann Intern Med 118 (10): 793-803, 1993.
12. Giovannucci E: How is individual risk for prostate cancer assessed? Hematol Oncol Clin North Am 10 (3): 537-48, 1996.
13. Neuhausen SL, Skolnick MH, Cannon-Albright L: Familial prostate cancer studies in Utah. Br J Urol 79 (Suppl 1): 15-20, 1997.
14. Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995.
15. Gaff CL, Aragona C, MacInnis RJ, et al.: Accuracy and completeness in reporting family history of prostate cancer by unaffected men. Urology 63 (6): 1111-6, 2004.
16. Weinrich SP, Faison-Smith L, Hudson-Priest J, et al.: Stability of self-reported family history of prostate cancer among African American men. J Nurs Meas 10 (1): 39-46, 2002 Spring-Summer.
17. Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004.
18. Stanford JL, Stephenson RA, Coyle LM, et al., eds.: Prostate Cancer Trends 1973-1995. National Cancer Institute, 1999. NIH Pub. No. 99-4543. Also available online. Last accessed November 22, 2022.
19. Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999.

Psychosocial Issues in Familial Prostate Cancer

Introduction

Research to date has included survey, focus group, and correlation studies on psychosocial issues related to prostate cancer risk. For more information about psychosocial issues associated with genetic counseling, see the Psychological Impact of Genetic Information/Test Results on the Individual section in Cancer Genetics Risk Assessment and Counseling. Genetic testing for pathogenic variants in genes associated with prostate cancer risk is now available and has the potential to identify those at increased risk of prostate cancer. Understanding the motivations of men who may consider genetic testing for inherited susceptibility to prostate cancer can help clinicians and researchers anticipate interest in testing. Further, these data may inform the nature and content of counseling strategies for men and their families, including consideration of the risks, benefits, decision-making issues, and informed consent for genetic testing.

Risk Perception

Knowledge about risk of prostate cancer is thought to be a factor influencing men's decisions to pursue prostate cancer screening and, possibly, genetic testing.[1] A study of 79 African American men (38 of whom had been diagnosed with prostate cancer and the remainder who were unaffected but at high risk of prostate cancer) completed a nine-item telephone questionnaire assessing knowledge about hereditary prostate cancer. On a scale of 0 to 9, with 9 representing a perfect score, scores ranged from 3.5 to 9 with a mean score of 6.34. The three questions relating to genetic testing were the questions most likely to be incorrect. In contrast, questions related to inheritance of prostate cancer risk were answered correctly by the majority of subjects.[2] Overall, knowledge of hereditary prostate cancer was low, especially concepts of genetic susceptibility, indicating a need for increased education. An emerging body of literature is now exploring risk perception for prostate cancer among men with and without a family history. Table 13 provides a summary of studies examining prostate cancer risk perception.

Table 13. Summary of Cross-Sectional Studies of Prostate Cancer Risk Perception

Study Population	Sample Size	Proportion of Study Population That Accurately Reported Their Risk	Other Findings
FDR = first-degree relative.
Unaffected men with a family history of prostate cancer[3]	120 men aged 40–72 y	40%
FDRof men with prostate cancer[4]	105 men aged 40–70 y	62%
Men with brothersaffectedwith prostate cancer[5]	111 men aged 33–78 y	Not available	38% of men reported their risk of prostate cancer to be the same or less than the average man
FDR of men with prostate cancer and a community sample[6]	56 men with an FDR with prostate cancer and 100 men without an FDR with prostate cancer all older than 40 y	57%	29% of men with an FDR thought that they were at the same risk as the average man, and 14% believed that they were at somewhat lower risk than average

Study conclusions vary regarding whether first-degree relatives (FDRs) of prostate cancer patients accurately estimate their prostate cancer risk. Some studies found that men with a family history of prostate cancer considered their risk to be the same as or less than that of the average man.[5,6] Other factors, including being married, have been associated with higher prostate cancer risk perception.[7] A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer.[3]

Anticipated Interest in Genetic Testing for Risk of Prostate Cancer

A number of studies summarized in Table 14 have examined participants' interest in genetic testing, if such a test were available for clinical use. Factors found to positively influence the interest in genetic testing include the following:

• Advice of their primary care physician.[8]
• Combination of emotional distress and concern about prostate cancer treatment effects.[9]
• Having children.[10]

Findings from these studies were not consistent regarding the influence of race, education, marital status, employment status, family history, and age on interest in genetic testing. Study participants expressed concerns about confidentiality of test results among employers, insurers, and family and stigmatization; potential loss of insurability; and the cost of the test.[8] These concerns are similar to those that have been reported in women contemplating genetic testing for breast cancer predisposition.[11,12,13,14,15,16] Concerns voiced about testing positive for a pathogenic variant in a prostate cancer susceptibility gene included decreased quality of life secondary to interference with sex life in the event of a cancer diagnosis, increased anxiety, and elevated stress.[8]

Table 14. Summary of Cross-Sectional Studies of Anticipated Interest in Prostate Cancer Susceptibility Genetic Testing

Study Population	Sample Size	Percent Expressing Interest in Genetic Testing	Other Findings
FDR = first-degree relative; PSA = prostate-specific antigen.
Prostate screening clinic participants[17]	342 men aged 40–97 y	89%	28% did not demonstrate an understanding of the concept of inherited predisposition to cancer
General population; 9% with positive family history[8]	12 focus groups with a total of 90 men aged 18–70 y	All focus groups
African American men[18]	320 men aged 21–98 y	87%	Most participants could not distinguish between genetic susceptibility testing and a prostate-specific antigen blood test
Men with and without FDRs with prostate cancer[9]	126 men aged >40 y; mean age 52.6 y	24% definitely; 50% probably
Swedish men with an FDR with prostate cancer[3]	110 men aged 40–72 y	76% definitely; 18% probably	89% definitely or probably wanted their sons to undergo genetic testing
Sons of Swedish men with prostate cancer[10]	101 men aged 21–65 y	90%; 100% of sons with two or three family members affected with prostate cancer	60% expressed worry about having an increased risk of prostate cancer
Healthy outpatient males with no history of prostate cancer[19]	400 men aged 40–69 y	82%
Healthy African American males with no history of prostate cancer[20]	413 African American men aged 40–70 y	87%	Belief in the efficacy of and intention to undergo prostate cancer screening was associated with testing interest
Healthy Australian males with no history of prostate cancer[21]	473 adult men	66% definitely; 26% probably	73% reported that they felt diet could influence prostate cancer risk
Males with prostate cancer and their unaffected male family members[22]	559 men with prostate cancer; 370 unaffected male relatives	45% of men affected with cancer; 56% of unaffected men	In affected men, younger age and test familiarity were predictors of genetic testing interest. In unaffected men, older age, test familiarity, and a PSA test within the last 5 y were predictors of genetic testing interest

Overall, these reports and a study that developed a conceptual model to look at factors associated with intention to undergo genetic testing [23] have shown a significant interest in genetic testing for prostate cancer susceptibility despite concerns about confidentiality and potential discrimination. These findings must be interpreted cautiously in predicting actual prostate cancer genetic test uptake once testing is available. In both Huntington disease and hereditary breast and ovarian cancers, hypothetical interest before testing was possible was much higher than actual uptake following availability of the test.[24,25]

In a sample comprised of undiagnosed men with and without a prostate cancer–affected FDR, older age and lower education levels were associated with lower levels of prostate cancer–specific distress (as measured by the 11-item Prostate Cancer Anxiety Subscale of the Memorial Anxiety Scale for Prostate Cancer); higher distress was associated with having more urinary symptoms.[26] In the same study, men with a prostate cancer–affected FDR who perceived their relative's cancer as more threatening and who had a relative deceased from the disease reported higher distress. In general, prostate cancer–specific distress levels were low for both groups of men.

Screening for Prostate Cancer in Individuals at Increased Familial Risk

The proportion of prostate cancers attributed to hereditary causes is estimated to be 5% to 10%.[27] An individual's prostate cancer risk increases when he has a large number of blood relatives with prostate cancer and when he has family members with young ages of prostate cancer onset.[28] There is considerable controversy about the use of serum prostate-specific antigen (PSA) measurement and digital rectal exam for prostate cancer early detection in the general population, with different organizations suggesting significantly different screening algorithms and age recommendations. For more information about prostate cancer screening in the general population, see Prostate Cancer Screening, and for more information about screening for individuals with hereditary prostate cancer syndromes, see the Screening and Prevention Interventions in Familial Prostate Cancer section. This variation is likely to add to patient and provider confusion about recommendations for screening by members of hereditary cancer families or FDRs of prostate cancer patients. Psychosocial questions of interest include what individuals at increased risk understand about hereditary risk, whether informational interventions are associated with increased uptake of prostate cancer screening behaviors, and what the associated quality-of-life implications of screening are for individuals at increased risk. Also of interest is the role of the primary care provider in helping those at increased risk identify their risk and undergo age- and family-history–appropriate screening.

Screening behaviors

In most cancers, the goal of improved knowledge of hereditary risk can be translated rather easily into a desired increase in adherence to approved and recommended (if not proven) screening behaviors. This complicates prostate cancer screening, because there is a lack of clear recommendations for both high-risk men and men in the general population. For more information, see the Screening section. In addition, controversy exists with regard to the value of early diagnosis of prostate cancer. This creates uncertainty for patients and providers. It also challenges the psychosocial factors related to screening behavior.

Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk based on family history; these are summarized in Table 15. In general, results appear contradictory regarding whether men with a family history are more likely to be screened than those not at risk and whether the screening is appropriate for their risk status. Furthermore, most of the studies had relatively small numbers of subjects, and the criteria for screening were not uniform, making generalization difficult.

Table 15. Summary of Studies of Behavioral Correlates for Prostate Cancer Screening

Study Population	Sample Size	Percent Undergoing Screening	Predictive Correlates for Screening Behavior
AAHPC = African American Hereditary Prostate Cancer Study Network; DRE = digital rectal exam; FDR = first-degree relative; NHIS = National Health Interview Survey; PSA = prostate-specific antigen.
Unaffected men with at least one FDR with prostate cancer[29]	82 men (aged ≥40 y; mean age 50.5 y)	PSA:	Aged >50 y
			Annual income ≥ U.S. $40,000
		50% reported PSA screening within the previous 14 mo	History of PSA screening before study enrollment
			Higher levels of self-efficacy and response efficacy for undergoing prostate cancer screening
Sons of men with prostate cancer[30]	124 men (60 men with a history of prostate cancer aged 38–84 y, median age 59 y; 64 unaffected men aged 31–78 y, median age 55 y)	PSA:	39.4% patient request
		— Unaffected men: 95.3% reported ever having a PSA test
		— Affected men: 71.7% reported ever having a PSA test before diagnosis
		DRE:
		— Unaffected men: 96.9% reported ever having a DRE
		— Affected men: 91.5% reported ever having a DRE before diagnosis	35.6% physician request
		Both PSA and DRE:
		— Unaffected men: 93.8% had both procedures
		— Affected men: 70.0% reported having both procedures before diagnosis
Unaffected men with and without an FDR with prostate cancer[6]	156 men aged ≥40 y (56 men with an FDR; 100 men without an FDR)	PSA:	Older age
		63% reported ever having a PSA test
			FDRs reported higher disease vulnerability and less belief in disease prevention, but this did not result in increased prostate cancer screening when compared with those without an FDR
		DRE:
		86% reported ever having a DRE
Unaffected Swedish men from families with a 50% probability of carrying a pathogenic variant in a dominant prostate cancer susceptibility gene[3]	110 men aged 50–72 y	68% of men aged ≥50 y were screened for prostate cancer	More relatives with prostate cancer
			Low score on the avoidance subscales of the Impact of Event Scale[31]
Brothers or sons of men with prostate cancer[32]	136 men aged 40–70 y (72% were African American men)	PSA:	More relatives with prostate cancer
		72% reported ever having a PSA test
		— 73% within 1 y	Older age
		— 23% 1–2 y ago
		— 4% >2 y ago
		DRE:	Urinary symptoms
		90% reported ever having had a DRE
		— 60% within 1 y
		— 23% 1–2 y ago	71% reported their physician had spoken to them about prostate cancer screening
		— 17% >2 y ago
Unaffected men with and without an FDR with prostate cancer[33]	166 men aged 40–80 y (83 men with an FDR; 83 men with no family history)	PSA:	Family history of prostate cancer
		— FDR: 72% reported ever having had a PSA test
		— No family history: 53% reported ever having had a PSA test	Greater perceived vulnerability to developing prostate cancer
French brothers or sons of men with prostate cancer[34]	420 men aged 40–70 y	PSA:	Younger age
			More relatives with prostate cancer
			Increased anxiety
		88% adhered to annual PSA screening	Married
			Higher education
			Previous history of prostate cancer screening
Data from unaffected African American men participating in AAHPC and data from the 1998 and 2000 NHIS[35]	Unaffected men aged 40–69 y:	PSA:	Younger age
		AAHPC Cohort:
		— 45% reported ever having had a PSA test
	— AAHPC Cohort: 134 men	African American men in 2000 NHIS:
		— 65% reported ever having had a PSA test
		DRE:
	— NHIS 1998 Cohort: 5,583 men (683 African American, 4,900 White)	AAHPC Cohort:	Fewer relatives with prostate cancer
		— 35% reported ever having had a DRE
		African American men in 1998 NHIS:
	— NHIS 2000 Cohort: 3,359 men (411 African American, 2,948 White)	— 45% reported ever having had a DRE
Unaffected African American men who participated in the 2000 NHIS[36]	736 men aged ≥45 y	PSA:	Older age (≥50 y)
			Private or military health insurance
		48% reported ever having had a PSA test	Fair or poor health status
			Family history of prostate cancer

Psychosocial outcomes of screening in individuals at increased familial risk

Concern about developing prostate cancer: Although up to 50% of men in some studies who were FDRs of prostate cancer patients expressed some concern about developing prostate cancer,[5] the level of anxiety reported is typically relatively low and is related to lifetime risk rather than short-term risk.[3,5] The concern is also higher in men who are younger than his FDR was at the time when their prostate cancer was diagnosed.[5] Unmarried FDRs worried more about developing prostate cancer than did married men.[5] Men with higher levels of concern about developing prostate cancer also had higher estimates of personal prostate cancer risk and had a larger number of relatives diagnosed with prostate cancer.[5] In a Swedish study, only 3% of the 110 men surveyed said that worry about prostate cancer affected their daily life "fairly much," and 28% said it affected their daily life "slightly."[3]

Baseline distress levels: Among men who self-referred for free prostate cancer screening, general and prostate cancer–related distress did not differ significantly between men who were FDRs of prostate cancer patients and men who were not.[37] Men with a family history of prostate cancer in the study had higher levels of perceived risk. In a Swedish study, male FDRs of prostate cancer patients who reported more worry about developing prostate cancer had higher Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores than men with lower levels of worry. In that study, the average HADS depression and anxiety scores among FDRs were at the 75^th percentile. Depression was associated with higher levels of personal risk overestimation.[3]

Distress experienced during prostate cancer screening: A study measured the anxiety and general quality of life experienced by 220 men with a family history of prostate cancer while undergoing prostate cancer screening with PSA tests.[32] In this group, 20% of the men experienced a moderate deterioration in their anxiety scores, and 20% experienced a minimal deterioration in health-related quality of life (HRQOL). The average period between assessments was 35 days, which encompassed PSA testing and a wait for results that averaged 15.6 days. Only men with normal PSA values (4 ng/mL or less) were assessed. Factors associated with deterioration in HRQOL included being age 50 to 60 years, having more than two relatives with prostate cancer, having an anxious personality, being well-educated, and having no children presently living at home. These authors stress that analysis of the impact of screening on FDRs should not rely solely on mean changes in scores, which may "mask diversity among responses, as illustrated by the proportion of subjects worsening during the screening process." Given that these were men receiving what was considered a normal result and that a subset of men experienced screening-associated distress, this study suggests that interventions to reduce screening-related distress may be needed to encourage men at increased hereditary risk to comply with repeated requests for screening.

A study in the United Kingdom assessed predictors of psychological morbidity and screening adherence in FDRs of men with prostate cancer participating in a PSA screening study. One hundred twenty-eight FDRs completed measures assessing psychological morbidity, barriers, benefits, knowledge of PSA screening, and perceived susceptibility to prostate cancer. Overall, 18 men (14%) scored above the threshold for psychiatric morbidity, consistent with normal population ranges. Cancer worry was positively associated with health anxiety, perceived risk, and subjective stress. However, psychological morbidity did not predict PSA screening adherence. Only past screening behavior was found to be associated with PSA screening adherence.[38]

References:

1. Weinrich SP, Weinrich MC, Boyd MD, et al.: The impact of prostate cancer knowledge on cancer screening. Oncol Nurs Forum 25 (3): 527-34, 1998.
2. Weinrich S, Vijayakumar S, Powell IJ, et al.: Knowledge of hereditary prostate cancer among high-risk African American men. Oncol Nurs Forum 34 (4): 854-60, 2007.
3. Bratt O, Damber JE, Emanuelsson M, et al.: Risk perception, screening practice and interest in genetic testing among unaffected men in families with hereditary prostate cancer. Eur J Cancer 36 (2): 235-41, 2000.
4. Cormier L, Kwan L, Reid K, et al.: Knowledge and beliefs among brothers and sons of men with prostate cancer. Urology 59 (6): 895-900, 2002.
5. Beebe-Dimmer JL, Wood DP, Gruber SB, et al.: Risk perception and concern among brothers of men with prostate carcinoma. Cancer 100 (7): 1537-44, 2004.
6. Miller SM, Diefenbach MA, Kruus LK, et al.: Psychological and screening profiles of first-degree relatives of prostate cancer patients. J Behav Med 24 (3): 247-58, 2001.
7. Montgomery GH, Erblich J, DiLorenzo T, et al.: Family and friends with disease: their impact on perceived risk. Prev Med 37 (3): 242-9, 2003.
8. Doukas DJ, Fetters MD, Coyne JC, et al.: How men view genetic testing for prostate cancer risk: findings from focus groups. Clin Genet 58 (3): 169-76, 2000.
9. Diefenbach MA, Schnoll RA, Miller SM, et al.: Genetic testing for prostate cancer. Willingness and predictors of interest. Cancer Pract 8 (2): 82-6, 2000 Mar-Apr.
10. Bratt O, Kristoffersson U, Lundgren R, et al.: Sons of men with prostate cancer: their attitudes regarding possible inheritance of prostate cancer, screening, and genetic testing. Urology 50 (3): 360-5, 1997.
11. Lee SC, Bernhardt BA, Helzlsouer KJ: Utilization of BRCA1/2 genetic testing in the clinical setting: report from a single institution. Cancer 94 (6): 1876-85, 2002.
12. Jacobsen PB, Valdimarsdottier HB, Brown KL, et al.: Decision-making about genetic testing among women at familial risk for breast cancer. Psychosom Med 59 (5): 459-66, 1997 Sep-Oct.
13. Lerman C, Schwartz MD, Lin TH, et al.: The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 65 (3): 414-20, 1997.
14. Rimer BK, Schildkraut JM, Lerman C, et al.: Participation in a women's breast cancer risk counseling trial. Who participates? Who declines? High Risk Breast Cancer Consortium. Cancer 77 (11): 2348-55, 1996.
15. Struewing JP, Lerman C, Kase RG, et al.: Anticipated uptake and impact of genetic testing in hereditary breast and ovarian cancer families. Cancer Epidemiol Biomarkers Prev 4 (2): 169-73, 1995.
16. Lerman C, Daly M, Masny A, et al.: Attitudes about genetic testing for breast-ovarian cancer susceptibility. J Clin Oncol 12 (4): 843-50, 1994.
17. Miesfeldt S, Jones SM, Cohn W, et al.: Men's attitudes regarding genetic testing for hereditary prostate cancer risk. Urology 55 (1): 46-50, 2000.
18. Weinrich S, Royal C, Pettaway CA, et al.: Interest in genetic prostate cancer susceptibility testing among African American men. Cancer Nurs 25 (1): 28-34, 2002.
19. Doukas DJ, Li Y: Men's values-based factors on prostate cancer risk genetic testing: a telephone survey. BMC Med Genet 5: 28, 2004.
20. Myers RE, Hyslop T, Jennings-Dozier K, et al.: Intention to be tested for prostate cancer risk among African-American men. Cancer Epidemiol Biomarkers Prev 9 (12): 1323-8, 2000.
21. Cowan R, Meiser B, Giles GG, et al.: The beliefs, and reported and intended behaviors of unaffected men in response to their family history of prostate cancer. Genet Med 10 (6): 430-8, 2008.
22. Harris JN, Bowen DJ, Kuniyuki A, et al.: Interest in genetic testing among affected men from hereditary prostate cancer families and their unaffected male relatives. Genet Med 11 (5): 344-55, 2009.
23. Li Y, Doukas DJ: Health motivation and emotional vigilance in genetic testing for prostate cancer risk. Clin Genet 66 (6): 512-6, 2004.
24. Meiser B, Dunn S: Psychological impact of genetic testing for Huntington's disease: an update of the literature. J Neurol Neurosurg Psychiatry 69 (5): 574-8, 2000.
25. Lerman C, Shields AE: Genetic testing for cancer susceptibility: the promise and the pitfalls. Nat Rev Cancer 4 (3): 235-41, 2004.
26. McDowell ME, Occhipinti S, Gardiner RA, et al.: Prevalence and predictors of cancer specific distress in men with a family history of prostate cancer. Psychooncology 22 (11): 2496-504, 2013.
27. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.
28. Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.
29. Vadaparampil ST, Jacobsen PB, Kash K, et al.: Factors predicting prostate specific antigen testing among first-degree relatives of prostate cancer patients. Cancer Epidemiol Biomarkers Prev 13 (5): 753-8, 2004.
30. Bock CH, Peyser PA, Gruber SB, et al.: Prostate cancer early detection practices among men with a family history of disease. Urology 62 (3): 470-5, 2003.
31. Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom Med 41 (3): 209-18, 1979.
32. Cormier L, Reid K, Kwan L, et al.: Screening behavior in brothers and sons of men with prostate cancer. J Urol 169 (5): 1715-9, 2003.
33. Jacobsen PB, Lamonde LA, Honour M, et al.: Relation of family history of prostate cancer to perceived vulnerability and screening behavior. Psychooncology 13 (2): 80-5, 2004.
34. Roumier X, Azzouzi R, Valéri A, et al.: Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer. Eur Urol 45 (3): 280-5; author reply 285-6, 2004.
35. Weinrich SP: Prostate cancer screening in high-risk men: African American Hereditary Prostate Cancer Study Network. Cancer 106 (4): 796-803, 2006.
36. Ross LE, Uhler RJ, Williams KN: Awareness and use of the prostate-specific antigen test among African-American men. J Natl Med Assoc 97 (7): 963-71, 2005.
37. Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999.
38. Sweetman J, Watson M, Norman A, et al.: Feasibility of familial PSA screening: psychosocial issues and screening adherence. Br J Cancer 94 (4): 507-12, 2006.

Changes to This Summary (03 / 17 / 2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Prostate Cancer are:

• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Veda N. Giri, MD (Yale University)
• Suzanne C. O'Neill, PhD (Georgetown University)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• Mark Pomerantz, MD (Dana-Farber Cancer Institute)
• John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
• Charite Ricker, MS, CGC (University of Southern California)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Prostate Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389227]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2023-03-17