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.
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).
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.
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 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.
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. Refer to OMIM for more information.
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. Refer to the Cancer Genetics Overview summary for more information about variant classification.
The public health burden of prostate cancer is substantial. A total of 248,530 new cases of prostate cancer and 34,130 deaths from the disease are anticipated in the United States in 2021, making it the most frequent nondermatologic cancer among U.S. males. 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.
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. 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. A 50% prevalence of latent prostate cancer was found by age 60 years in men of African descent, age 80 years in Caucasian men, and age 90 years in Asian men. 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.
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. 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/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). Non-Hispanic black men in the United States, however, have the highest incidence of prostate cancer in the world (171.6 cases/100,000 men). 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). Within the United States, non-Hispanic black men have an almost 80% higher incidence rate than non-Hispanic white men. Non-Hispanic black men have been reported to have more than twice the rate of prostate cancer–specific death (38.3/100,000 men) compared with non-Hispanic white men (17.9/100,000 men).
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. 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 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 451 for men 49 years or younger, 1 in 55 for men aged 50 through 59 years, 1 in 20 for men aged 60 through 69 years, and 1 in 12 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 8.
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. 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. 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.
The risk of developing prostate cancer is dramatically higher among non-Hispanic blacks (171.6 cases/100,000 men) compared with other racial groups in the United States (non-Hispanic white, 97.7 cases/100,000 men; Asian/Pacific Islander, 53.8 cases/100,000 men; American Indian/Alaska Native, 67.7 cases/100,000 men; and Hispanic/Latino, 85.6 cases/100,000 men). Prostate cancer mortality rates in non-Hispanic blacks (38.7/100,000 men) are also more than double those of other racial groups in the United States (non-Hispanic white, 17.9/100,000 men; Asian/Pacific Islander, 8.8/100,000 men; American Indian/Alaska Native, 18.5/100,000 men; and Hispanic/Latino, 15.6/100,000 men). Globally, prostate cancer incidence and mortality rates also vary widely country to country. 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.
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. (Refer to Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)
|Risk Group||RR for Prostate Cancer (95% CI)|
|CI = confidence interval; FDR = first-degree relative.|
|a Adapted from Kiciński et al.|
|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. 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. 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. This is consistent with findings from previous cohorts, 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] (Refer to the BRCA1 and BRCA2 section of this summary for more information.) 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. 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. (Refer to the Defining Lynch syndrome families section in the PDQ summary on Genetics of Colorectal Cancer for a description of Amsterdam I and II criteria.)
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. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age and stage at diagnosis and specific family cancer history patterns.[37,38] For a summary of the current criteria for genetic testing in men with or at risk of prostate cancer, refer to 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 Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto), 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 Americans than among African Americans or whites. 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.
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. 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). 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 variants and single nucleotide variants across the genome that have been found to have an association with prostate cancer risk. Refer to the National Human Genome Research Institute GWAS catalog for information about these associations and to the Clinical Application of Genetic Testing for Inherited Prostate Cancer section of this summary for information about genetic testing for prostate cancer risk.
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.
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 (SIRbladder, 0.76; SIRrectal, 0.74).
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%).
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.
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.
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). 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. 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. 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]).
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). 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.
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. 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.
Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended 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. The clinical role of pathogenic variants that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Clinical Application of Genetic Testing for Inherited Prostate Cancer section of this summary for more information about these genes.) 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.
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:
Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment. One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families. Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:
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, 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. 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 to be identified from a linkage study was reported. An initial linkage signal in the 17q21-22 region followed by targeted sequencing 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 in affected men (47%) was higher than 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. 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) associated with the HOXB13 G84E variant, although the frequency of the risk allele varied substantially across countries with the highest prevalence in the Nordic countries. The utility of testing for the G84E variant for prostate cancer screening needs to be determined. (Refer to the HOXB13 section of this summary for more information.)
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. 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. 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. 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. 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), 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]
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.
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. 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. 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. Because somatic mutations in CDH1 have been implicated in the development of invasive malignancies in a number of different cancers, 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% confidence interval [CI], 1.11–1.60). A subsequent meta-analysis confirmed a modest association with the CDH1 -160C/A polymorphism. 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.
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, p53, 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 is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry. 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 Americans. 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:
An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry. As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS. (Refer to the GWAS section of this summary for more information.)
Genome-wide Association Studies
Introduction to GWAS
Genome-wide searches have successfully identified susceptibility alleles for many complex diseases, including prostate cancer. 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 case compared to 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 and validated in independent cohorts (refer to the National Human Genome Research Institute GWAS catalog and ).[93,94,95] These studies have revealed 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 compared with older prostate cancer cases and compared with public controls. However, the findings should be qualified with a few important considerations:
The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.
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%.
Since the discovery of prostate cancer risk loci at 8q24, more than 100 variants at other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. 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. 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. Another study examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls. 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. 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.
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 in other studies.[120,121,122,123] Additionally, risk regions that are unique to these ancestral groups were identified (refer to 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. 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.[124,125]
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. 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).
Polygenic risk scores
In 2018, a polygenic risk score (PRS) based on 147 confirmed GWAS variants associated with prostate cancer was calculated in a study of more than 140,000 men. Compared with men with a PRS in the middle 50% of the distribution, those in the bottom 1% had a significantly lower risk (RR, 0.15), and those in the top 99% had a significantly higher risk (RR, 5.7). These findings suggest that the PRS could be a useful tool for risk stratification in the population. Another study of men with BRCA1/BRCA2 pathogenic variants calculated a PRS from 103 of the prostate cancer susceptibility variants, which showed to influence risk associated with these known variants. For example, variant carriers in the top 95% distribution of the PRS had the highest predicted risk of developing prostate cancer. Further studies are needed to determine whether the PRS will provide useful clinical information for risk stratification in the small subset of men who have BRCA1/BRCA2 pathogenic or likely pathogenic variants (or men with other rare genetic variants in high-risk cancer genes, such as those associated with DNA repair deficiency or Lynch syndrome).
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. 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. PRSs have been shown to be additive to risk attributed to rare pathogenic alleles, including BRCA1/BRCA2 and HOXB13. Because the penetrance of most rare pathogenic alleles associated with prostate cancer is often in the moderate range, the use of GWAS SNVs in understanding disease penetrance warrants further study.
GWAS findings to date account for only 30% of the estimated 58% of the heritable risk of disease. In addition, around 6% of the familial RR of prostate cancer has been attributed to rare genetic variants. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of less frequent and rarer alleles with higher ORs for risk. Research focused on the associated risk of prostate cancer and the predictability of PRSs is ongoing.
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.[133,134,135,136,136,137,138,139,140,141] As GWAS elucidate these networks, it is hoped that new therapies and chemopreventive strategies will follow.
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. 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 Variants 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.[143,144,145,146,147,148,149] Next, as GWAS revealed prostate cancer risk SNVs, several research teams sought to determine whether certain overall risk SNVs were also associated with aggressiveness.[150,151,152,153,154,155,156,157]
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). 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.[159,160] 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. Similarly, in a smaller study assessing prostate cancer–specific mortality (196 lethal cases, 368 long-term survivors), no variants were significantly associated with outcome. 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. 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. 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. 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, an updated analysis of those cohorts is under way.
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] Identification of men for inherited prostate cancer genetic testing is based upon family history criteria, personal/disease characteristics, and tumor sequencing results. Actual genes to test vary on the basis of specific guidelines or consensus conference recommendations. The National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Cancer guideline is focused on BRCA1/BRCA2 testing on the basis of various testing criteria. The NCCN Prostate Cancer treatment guideline states to test BRCA1/BRCA2, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2 for men meeting specific testing indications. A 2017 consensus conference addressed the role of genetic testing for inherited prostate cancer. Family history–based indications for testing included testing for BRCA1/BRCA2, HOXB13, or DNA mismatch repair (MMR) genes. Tumor sequencing with potential findings of germline variants in BRCA1/BRCA2 or DNA MMR genes, as well as other genes, is recommended for confirmatory germline testing. Somatic findings for which germline testing is considered include:
HOXB13 and ATM had lower level of consensus for testing on the basis of tumor sequencing. Men with metastatic castration-resistant prostate cancer were recommended to undergo genetic testing for BRCA1/BRCA2 (higher level of consensus) and ATM (moderate level of consensus). A second consensus conference focused on advanced prostate cancer stated that among panelists that recommended genetic testing on the basis of various criteria, there was agreement to use large panel testing including homologous recombination and DNA MMR genes. Available genetic testing indications from guidelines and consensus conferences are shown in Table 2.
|||Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2018)a||Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2020)b||NCCN Prostate Cancer (Version 1.2020)c||NCCN Prostate Cancer Early Detection (Version 2.2019)d||European Advanced Prostate Cancer Consensus Conference (Gillessen et al. 2017)e|
|dMMR = mismatch repair deficient; FDR = first-degree relative; HBOC = hereditary breast and ovarian cancer; MSI = microsatellite instability; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.|
|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 guideline focuses on testing forBRCA1/BRCA2pathogenic variants.|
|c NCCN Prostate Cancer guideline specifies that homologous recombination gene pathogenic variants and DNA MMR gene pathogenic variants include variants in the following genes:BRCA1,BRCA2,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6, andPMS2. Additional genes may be appropriate depending on the clinical context.|
|d NCCN Prostate Cancer Early Detection guideline does not specifically state which genes to test, but describes consideration ofBRCA1/BRCA2status and the status of other cancer risk genes when discussing prostate cancer screening.|
|e 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; and Lynch syndrome||Personal history of Gleason score ≥7 prostate cancer with: ≥1 biologic relative with ovarian, pancreatic, or metastatic prostate cancer at any age or breast cancer ≤50 y; or ≥2 biologic relatives with breast or prostate cancer (any grade) at any age; orAshkenazi Jewishancestry||≥3 cancers on the same side of the family, especially diagnoses ≤50 y: bile duct, breast, colorectal, endometrial, gastric, kidney, melanoma, ovarian, pancreatic, prostate (but not clinically localized Grade Group 1), small bowel, or urothelial cancer||None provided||Positive family history of prostate cancer|
|Men affected with prostate cancer with >2 close biologic relatives with a cancer associated with HBOC; hereditary prostate cancer, and Lynch syndrome||Ashkenazi Jewish ancestry||Positive family history of other cancer syndromes (HBOC and/or pancreatic cancer and/or Lynch syndrome)|
|Prostate cancer diagnosed <55 y in anFDR||Brother, father, or multiple family members with prostate cancer <60 y|
|Death <60 y from prostate cancer in an FDR||Brother, father, or multiple family members who died of prostate cancer|
|Disease Characteristics||All men with metastatic prostate cancer||Personal history of metastatic or intraductal prostate cancer (radiographic evidence or biopsy proven)||Men with high-/very-high-risk regional, or metastatic disease and any men with prostate cancer with intraductal histology||None provided||Men with newly diagnosed metastatic prostate cancer (62% of panel voted in favor ofgenetic counseling /testing in a minority of selected patients)|
|Prostate cancer diagnosed <55 y||Prostate cancer diagnosed <60 y|
|Tumor Characteristics||Men with prostate cancer whose somatic testing reveals the possibility of a germline variant in a cancer risk gene||A mutation identified on tumor genomic testing that has clinical implications if also identified in the germline||Consider tumor testing for homologous recombination gene pathogenic variants and for MSI or dMMR in regional and metastatic disease||None provided|
|Screening in BRCA1Carriers||Follow NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic guidelines||Consider prostate cancer screening starting at age 40 y||None provided||Consider beginning shared decision making about PSA screening at age 40 y|
|Interval of screening determined by baseline PSA level as specified in NCCN Prostate Cancer Early Detection Version 2.2019||Consider screening at annual intervals rather than every other year|
|Screening in BRCA2 Carriers||Baseline PSA >40 y or 10 years prior to the earliest age of prostate cancer in the family||Recommend prostate cancer screening starting at age 40 y||None provided||Consider beginning shared decision making about PSA screening at age 40 y|
|Interval of screening determined by baseline PSA level||Interval of screening determined by baseline PSA level as specified in NCCN Prostate Cancer Early Detection Version 2.2019||Consider screening at annual intervals rather than every other year|
|Screening in HOXB13 Carriers||Baseline PSA >40 y or 10 years prior to the earliest age of prostate cancer in the family||None provided||None provided||None provided|
|Interval of screening determined by baseline PSA level|
Multigene (Panel) Testing in Prostate Cancer
Since the availability of next-generation sequencing (NGS) and the elimination of patent restrictions, several clinical laboratories now offer genetic testing through multigene panels at a cost comparable to single-gene testing. A caveat is the possible finding of a variant of uncertain significance, where the clinical significance remains unknown. (Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations, and research examining the use of multigene testing.) This section summarizes the evidence for additional genes that may be on prostate cancer susceptibility 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. 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. A second study involved a larger cohort of 3,607 men with prostate cancer, some of whom had been included in the prior publication. 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%. 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). 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. 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.
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. 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 genes with some association with prostate cancer risk is now available and has the potential to identify men at increased risk of prostate cancer. 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, in the MMR genes. In addition, pathogenic variants in HOXB13 are reported to account for a small proportion of hereditary prostate cancer. This section summarizes the evidence for the genes mentioned above and additional genes that may be on prostate cancer susceptibility panel tests.
Refer to the Clinical study of genome-wide association studies (GWAS) findings section of this summary for information about polygenic risk scores (PRS) based on common inherited single nucleotide variants (SNVs).
Studies of male carriers of BRCA1 and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers. Prostate cancer, in particular, has been observed at higher rates in male carriers of BRCA2 pathogenic variants than in the general population.
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.
|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; 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)||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)||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)||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)||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)||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|
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.
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). 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.[20,21,22] 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% confidence interval [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.[23,24,25,26] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) 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. 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.
|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.|
|Guisti et al. (2003)||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)||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)||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)||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.
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.
|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)||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)||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)||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).[31,32,34] 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.
|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)||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)||266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; median age at prostate cancer diagnosis, 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)||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)||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)||913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; 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)||Prospective cohort of men withBRCA1(n = 376) orBRCA2(n = 447) pathogenic variants from the UK and Ireland; median follow-up, 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.
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.
|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)||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)||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)||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)||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)||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)||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)||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). The prostate cancers identified covered the spectrum of Gleason scores from less than 6 to greater than 8; however, they differed by gene:
These studies suggest that prostate cancer in carriers of BRCA pathogenic variants may be associated with features of aggressive disease, including higher Gleason score, higher prostate-specific antigen (PSA) level at diagnosis, and higher tumor stage and/or grade at diagnosis, a finding that warrants consideration as patients undergo cancer risk assessment and genetic counseling. 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.
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. The case-control studies summarized in Table 8 further assess this observation.
|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)||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)||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)||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)||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)||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)||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. 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. 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. 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.
HOXB13 is the first hereditary prostate cancer gene identified. The G84E variant has been extensively studied for prostate cancer risk.
Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer. 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. 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).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:
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. 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.[52,54,55,56,57,58,59] This pathogenic variant appears to be restricted to white men, primarily of European descent.[52,54,55,56] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases. 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.
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. 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. 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). 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). 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 whites (OR, 2.673; 95% CI, 1.920–3.720), especially those of European descent. No association was found for breast or colorectal cancer. 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. In addition, one study identified no men of AJ ancestry who carried the G84E pathogenic variant. 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). 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). 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.
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. 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). This information is important in developing gene tests for HOXB13 pathogenic variants in broader populations.
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. Another study from Australia reported an age-specific cumulative risk of prostate cancer of up to 60% by age 80 years. 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.
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, and duodenal cancers; and transitional cell cancers of the ureter and renal pelvis. Reports have suggested that prostate cancer may be observed in men harboring an MMR gene pathogenic variant.[71,72] 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. 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. 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. Other studies are attempting to characterize rates of prostate cancer in Lynch syndrome families and correlate molecular features with prostate cancer risk.
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. 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. 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). 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.
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. 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.
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 heterozygote carriers of ATM variants. In the presence of DNA damage, the ATM protein is involved in mediating cell cycle arrest, DNA repair, and apoptosis. Given evidence of other cancer risks in heterozygote carriers, evidence of an association with prostate cancer susceptibility continues to emerge. (Refer to the ATM section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about ATM and breast cancer.) A prospective case series of 10,317 Danish individuals with 36 years of follow-up, during which 2,056 individuals developed cancer, found that Ser49Cys was associated with prostate cancer (HR, 2.3; 95% CI, 1.1–5.0). A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found that 1.6% (11 of 692) had an ATM pathogenic variant. Multiple independent reports have shown that the ATM P1054R variant is associated with prostate cancer.[11,84,85] The Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium demonstrated an OR of 1.16 (95% CI, 1.10–1.22) for association with this risk variant, which is found in 2% of Europeans.
CHEK2 has also been investigated for a potential association with prostate cancer risk. 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. 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. 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). Further studies of CHEK2 in large diverse populations are warranted.
TP53 has also been investigated for a potential association with prostate cancer risk. 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. 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). 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).
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.
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. 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. The risk of prostate cancer in NBN 657del5 carriers is influenced by the genotype at the E185Q polymorphism.
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 MSH2, induce methylation of the MSH2 promoter resulting in MSH2 protein loss. (Refer to the EPCAM section in the PDQ summary on Genetics of Colorectal Cancer for a more detailed discussion about EPCAM and Lynch syndrome.) Pathogenic variants in MSH2 that are associated with Lynch syndrome were found to be associated with increased risk of prostate cancer. (Refer to the Mismatch repair genes section of this summary for information about MSH2 and prostate cancer risk.) Thus far, studies ascertaining the spectrum of germline pathogenic variants in men with prostate cancer have not identified pathogenic variants in EPCAM.
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. 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. 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.
|Study||Cohort||Germline Results for Prostate Cancer||Comments|
|mCRPC = metastatic castration-resistant prostate cancer.|
|a Potential overlap of cohorts.|
|Robinson et al. (2015)a||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||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)||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.Table 10 summarizes some of the published precision oncology and precision management studies.
|ADT = androgen deprivation therapy; AR = androgen receptor; CSS = cause-specific survival; DDR = DNA damage repair; HR = hazard ratio; mCRPC = metastatic castration-resistant prostate cancer; mPC = metastatic prostate cancer; OS = overall survival; PFS = progression-free survival; PSA = prostate-specific antigen; RR = relative risk.|
|Annala et al. (2017)||319 men with mCRPC; performed germline sequencing of 22 DNA repair genes||24/319 (7.5%) had DDR germline pathogenic variants:||Patients with DNA repair defects had decreased responses to ADT:|
|—BRCA2: 16/319 (5.0%)||— Time from ADT initiation to mCRPC (mo): Germline positive, 11.8 (n = 22) vs. germline negative, 19.0 (n = 113) (P = .031).|
|—ATM: 1/319 (0.3%)||— PFS on first-line AR-targeted therapy (mo): Germline positive, 3.3 vs. germline negative, 6.2 (P = .01).|
|—BRCA1: 1/319 (0.3%)|
|—PALB2: 2/319 (0.6%)|
|Pomerantz et al. (2017)||141 men with mCRPC treated with carboplatinum and docetaxel||8/141 (5.7%) hadBRCA2variants||6/8 men withBRCA2germline variants (75%) had a PSA decline of 50% vs. 23/133 men withoutBRCA2germline variants (17%) (P< .001). A small case series (n = 3) supported a response to platinum chemotherapy with biallelic inactivation ofBRCA2, defined as either biallelic somaticBRCA2mutations or germline variants plus somaticBRCA2mutations.|
|Antonarakis et al. (2018)||172 men with mCRPC beginning treatment with abiraterone or enzalutamide||22/172 (12.8%) had DDR germline pathogenic variants:||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 (allP> .10). Study limited by the small number of patients (n = 9) withBRCA1/BRCA2/ATMvariants.|
|—BRCA1/BRCA2/ATM: 9/172 (5.2%)|
|Mateo et al. (2018)||390 men with mPC; retrospective chart review||60/390 (15.4%) had germline DDR pathogenic variants:||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 prostate cancer (61% in carriers vs. 54% in noncarriers).|
|— Median PFS on first-line abiraterone/enzalutamide (8.3 mo in both carriers and noncarriers).|
|— RR of prostate cancer on first-line abiraterone/enzalutamide (46% in carriers vs. 56% in noncarriers).|
|Castro et al. (2019)||419 men with mCRPC||68/419 (16.2%) had germline DDR pathogenic variants:||CSS betweenATM/BRCA1/BRCA2/PALB2carriers and noncarriers was not statistically significant (23.3 mo vs. 33.2 mo;P = .264). CSS was halved inBRCA2carriers (17.4 mo vs. 33.2 mo;P = .027), andBRCA2variants were identified as an independent prognostic factor for CSS (HR, 2.11;P = .033). Significant interactions betweenBRCA2status and treatment type (androgen signaling inhibitor vs. taxane therapy) were observed (CSS adjustedP = .014; PFS adjustedP = .005). CSS (24.0 mo vs. 17.0 mo) and PFS (18.9 mo vs. 8.6 mo) were greater inBRCA2carriers treated in first line with abiraterone or enzalutamide compared with taxanes.|
|—BRCA2: 14/419 (3.3%)|
|—ATM: 8/419 (1.9%)|
|—BRCA1: 4/419 (1%)|
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 a summary of available clinical practice guidelines for genetic testing in prostate cancer, refer to Table 2.
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 work-ups 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. (Refer to the PDQ Cancer Screening Overview summary for more information.) 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.
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 the PDQ Prostate Cancer Screening summary. 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.
|Screening Recommendation Source||Population||Test||Age Screening Initiated||Frequency||Comments|
|DRE = digital rectal exam; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.|
|a DRE is recommended in addition to PSA test for men with hypogonadism.|
|United States Preventive Services Task Force (2012)||N/A||N/A||N/A||N/A||No specific recommendation for high-risk populations (defined as black men and men with a prostate cancer family history).|
|American College of Physicians (2013)||African American men and men with first-degree relative diagnosed with prostate cancer, especially <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 family history of multiple family members with prostate cancer diagnosed <65 y||PSA||≥40 y|
|PSA level >2.5 µg/L may warrant annual screening|
|American Urological Association (2013)||African American men and men with a strong prostate cancer family history||PSA||>40 to <55 y||Individualized based on personal preferences and informed discussion regarding the uncertainty of benefit and associated harms.|
|American Cancer Society (2014)||African American men and/or men with a father or brother with prostate cancer diagnosed <65 y||PSA with or without DREa||≥45 y||Frequency depends on PSA level||Counseling consists of a review of the benefits and limitations of testing so that a clinician-assisted, informed decision about testing can be made.|
|Men with multiple family members with prostate cancer diagnosed <65 y||PSA with or without DREa||≥40 y||Frequency depends on PSA level|
|NCCN (2019)||African American men and men with family history of prostate cancer||N/A||N/A||N/A||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 and to consider screening at annual intervals rather than every other year.|
|NCCN (2020)||Men withBRCA1pathogenic variant||Not specified||Consider screening starting at age ≥40 y||Not specified|
|Men withBRCA2pathogenic variant||Not specified||≥40 y||Not specified|
|NCCN (2019)||Men with a personal or family history of high-risk germline pathogenic variant||Baseline PSA; strongly consider baseline DRE||45–75 y||Every 2–4 y if PSA level <1 ng/mL, DRE normal||Additional recommendations for men with a PSA level >3 ng/mL or very suspicious DRE and men older than 75 y. (Refer to page PROSD-2 of the NCCN guidelines for more information.) Referral to a cancer genetics professional is recommended for those with a known or suspected cancer susceptibility gene.|
|Every 1–2 y if PSA level 1–3 ng/mL, DRE normal|
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. 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, 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.
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 the PDQ summary on Prostate Cancer Prevention.
The purpose of this section is to describe current approaches to assessing and counseling patients about susceptibility to prostate cancer. Genetic counseling for men at increased risk of prostate cancer encompasses all of the elements of genetic counseling for other hereditary cancers. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) 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]Genetic testing for prostate cancer susceptibility is not available outside of the context of a research study. 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. 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. The three criteria include the following:
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. 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:
(Refer to the Documenting the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed description of taking a family history.)
Analysis of the family history generally consists of four components:
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. 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. Self-reported family history of prostate cancer, however, may not be reliably reported over time, 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:
The most definitive risk factors for prostate cancer are age, race, and family history. 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 regarding the state of the knowledge of 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. (Refer to the Risk Factors for Prostate Cancer section of this summary for a more detailed description of prostate cancer risk factors.)
The psychosocial assessment in this context might include evaluation of the following:
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.
Multigene (panel) tests for variants in genes associated with prostate cancer susceptibility are currently available and are increasingly being used in the clinic. (Refer to the Multigene [Panel] Testing in Prostate Cancer section for more information.) Although routine genetic testing of high-risk prostate cancer patients for inherited variants associated with the disease is not standard, many centers are studying the clinical utility of germline genetic testing and counseling in these patients.
Research to date has included survey, focus group, and correlation studies on psychosocial issues related to prostate cancer risk. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about psychological issues related to genetic counseling for cancer risk assessment.) Genetic testing for pathogenic variants in genes with some association with prostate cancer risk is now available and has the potential to identify those at increased risk of prostate cancer. Having an understanding of 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.
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. 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. 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 12 provides a summary of studies examining 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||120 men aged 40–72 y||40%|
|FDRof men with prostate cancer||105 men aged 40–70 y||62%|
|Men with brothersaffectedwith prostate cancer||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||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. A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer.
Anticipated Interest in Genetic Testing for Risk of Prostate Cancer
A number of studies summarized in Table 13 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:
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. 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.
|Study Population||Sample Size||Percent Expressing Interest in Genetic Testing||Other Findings|
|FDR = first-degree relative; PSA = prostate-specific antigen.|
|Prostate screening clinic participants||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||12 focus groups with a total of 90 men aged 18–70 y||All focus groups|
|African American men||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||126 men aged >40 y; mean age 52.6 y||24% definitely; 50% probably|
|Swedish men with an FDR with prostate cancer||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||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||400 men aged 40–69 y||82%|
|Healthy African American males with no history of prostate cancer||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||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||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  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. 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%, and the risk of prostate cancer increases with the number of blood relatives with prostate cancer and young age at onset of prostate cancer within families. There is considerable controversy in prostate cancer 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. (Refer to the PDQ summary on Prostate Cancer Treatment for more information about prostate cancer in the general population and the Interventions section of this summary for more information about inherited prostate cancer susceptibility.) 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.
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 is complicated for prostate cancer screening by the lack of clear recommendations for men in both high-risk and general populations. (Refer to the Screening section of this summary for more information.) In addition, controversy exists with regard to the value of early diagnosis of prostate cancer. This creates uncertainty for patients and providers and 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 14. 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.
|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||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||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.|
|— 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||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.|
|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||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.|
|Brothers or sons of men with prostate cancer||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.|
|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||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||420 men aged 40–70 y||PSA:||Younger age.|
|More relatives with prostate cancer.|
|88% adhered to annual PSA screening.||Married.|
|Previous history of prostate cancer screening.|
|Data from unaffected African American men participating in AAHPC and data from the 1998 and 2000 NHIS||Unaffected men aged 40–69 y:||PSA:||Younger age.|
|— 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.|
|— 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||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, 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. Unmarried FDRs worried more about developing prostate cancer than did married men. 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. 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."
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. 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 was at the 75th percentile. Depression was associated with higher levels of personal risk overestimation.
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. 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.
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.
Updated statistics with estimated new prostate cancer cases and deaths for 2021 (cited American Cancer Society as reference 1).
Updated statistics with incidence rates and mortality by race and ethnicity.
Updated statistics with age-specific probabilities of being diagnosed with prostate cancer in 2021.
Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk
Updated statistics for lifetime risk of prostate cancer (cited American Cancer Society as reference 4).
Added Polygenic risk scores as a new subsection title.
Clinical Application of Genetic Testing for Inherited Prostate Cancer
Added text to state that 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 than in BRCA1 carriers (cited Oh et al. as reference 19).
Prostate Cancer Risk Assessment
Updated statistics for lifetime risk of prostate cancer (cited American Cancer Society as reference 3).
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® - NCI's Comprehensive Cancer Database pages.
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 who care for cancer 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:
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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.
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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]
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Last Revised: 2021-02-26
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