This executive summary reviews the topics covered in the PDQ summary on the genetics of colorectal cancer (CRC), with hyperlinks to detailed sections below that describe the evidence on each topic.
Factors suggestive of a genetic contribution to CRC include the following: (1) a strong family history of CRC and/or polyps; (2) multiple primary cancers in a patient with CRC; (3) the existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of CRC, such as endometrial cancer; and (4) early age at diagnosis of CRC. Hereditary CRC is most commonly inherited in an autosomal dominant pattern, although two syndromes are inherited in an autosomal recessive pattern (MUTYH-associated polyposis and NTHL1).
At least three validated computer models are available to estimate the probability that an individual affected with cancer carries a pathogenic variant in a mismatch repair (MMR) gene associated with Lynch syndrome, the most common inherited CRC syndrome. These include the MMRpro, MMRpredict, and PREMM5 (PREdiction Model for gene Mutations) prediction models. Individuals with a quantified risk of 2.5% or greater on PREMM5 or 5% or greater on MMRpro and MMRpredict are recommended for genetic evaluation referral and testing.
Hereditary CRC has two well-described forms: (1) polyposis (including familial adenomatous polyposis [FAP] and attenuated FAP [AFAP], which are caused by pathogenic variants in the APC gene; and MUTYH-associated polyposis, which is caused by pathogenic variants in the MUTYH gene); and (2) Lynch syndrome (often referred to as hereditary nonpolyposis colorectal cancer), which is caused by germline pathogenic variants in DNA MMR genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM. Other CRC syndromes and their associated genes include oligopolyposis (POLE, POLD1), NTHL1, juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11). Many of these syndromes are also associated with extracolonic cancers and other manifestations. Serrated polyposis syndrome, which is characterized by the appearance of hyperplastic polyps, appears to have a familial component, but the genetic basis remains unknown. The natural history of some of these syndromes is still being described. Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC. In addition, most individuals with CRC diagnosed before age 50 years and without a family history of cancer do not have a pathogenic variant associated with an inherited cancer syndrome.
Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including CRCs, but the clinical utility of these findings remains uncertain.
It is becoming the standard of care at many centers that all individuals with newly diagnosed CRC are evaluated for Lynch syndrome through molecular diagnostic tumor testing assessing MMR deficiency. A universal screening approach to tumor testing is supported, in which all CRC cases are evaluated regardless of age at diagnosis or fulfillment of existing clinical criteria for Lynch syndrome. A more cost-effective approach has been reported whereby all patients aged 70 years or younger with CRC and older patients who meet the revised Bethesda guidelines are tested for Lynch syndrome. Tumor evaluation often begins with immunohistochemistry testing for the expression of the MMR proteins associated with Lynch syndrome or microsatellite instability (MSI) testing, BRAF testing, and MLH1 hypermethylation analyses.
Colonoscopy for CRC screening and surveillance is commonly performed in individuals with hereditary CRC syndromes and has been associated with improved survival outcomes. For example, surveillance of Lynch syndrome patients with colonoscopy every 1 to 2 years, and in one study up to 3 years, has been shown to reduce CRC incidence and mortality. Extracolonic surveillance is also a mainstay for some hereditary CRC syndromes depending on the other cancers associated with the syndrome. For example, regular endoscopic surveillance of the duodenum in FAP patients has been shown to improve survival.
Prophylactic surgery (colectomy) has also been shown to improve survival in patients with FAP. The timing and extent of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology. For patients with Lynch syndrome and a diagnosis of CRC, extended resection is associated with fewer metachronous CRCs and additional surgical procedures for colorectal neoplasia than in patients who undergo segmental resection for CRC. The surgical decision must consider the age of the patient, comorbidities, clinical stage of the tumor, sphincter function, and the patient's wishes.
Chemopreventive agents have also been studied in the management of FAP and Lynch syndrome. In FAP patients, celecoxib and sulindac have been associated with a decrease in polyp size and number. A double-blind, randomized, controlled trial evaluating the efficacy of sulindac plus an epidermal growth factor receptor inhibitor, erlotinib, versus placebo in FAP or AFAP patients with duodenal polyps suggested that erlotinib has the potential to inhibit duodenal polyps in FAP patients. An ongoing trial will determine whether lower doses of erlotinib alone will significantly reduce duodenal polyp burden. Aspirin use (600 mg daily) was shown to have a preventive effect on cancer incidence in Lynch syndrome patients in a large randomized trial; lower doses are being examined in an ongoing study.
Novel therapies that stimulate the immune system have been evaluated in MMR-deficient tumors, including those related to Lynch syndrome. The dense immune infiltration and cytokine-rich environment in MMR-deficient tumors may improve clinical outcomes. A critical pathway responsible for mediating tumor-induced immune suppression is the programmed cell death-1 (PD-1)–mediated checkpoint pathway. Two phase 2 studies using anti–PD-1 immune checkpoint inhibitors (pembrolizumab and nivolumab) demonstrated favorable outcomes, including progression-free survival, radiographic response rates, and disease control rates in metastatic CRC with MMR deficiency and MSI that had progressed on prior cytotoxic chemotherapy. Pembrolizumab has shown similar benefit in other noncolorectal cancers with MMR deficiency and MSI, but not in tumors that are microsatellite stable.
Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic counseling and genetic testing for Lynch syndrome and FAP varies widely across studies. Factors that have been associated with genetic counseling and testing uptake in Lynch syndrome families include having children, the number of affected relatives, perceived risk of developing CRC, and frequency of thoughts about CRC. Psychological studies have shown low levels of distress, particularly in the long term, after genetic testing for Lynch syndrome in both carriers and noncarriers. However, other studies have demonstrated the possibility of increased distress following genetic testing for FAP. Colon and gynecologic cancer screening rates have been shown to increase or be maintained among carriers of MMR pathogenic variants within the year after disclosure of results, while screening rates decrease among noncarriers. The latter is expected as the screening recommendations for unaffected individuals are those that apply to the general population. Studies measuring quality-of-life variables in FAP patients show normal-range results; however, these studies suggest that risk-reducing surgery for FAP may have negative quality-of-life effects for at least some proportion of those affected. Patients' communication with their family members about an inherited risk of CRC is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. 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 genetic 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.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women.
Estimated new cases and deaths from CRC in 2022 in the United States:[
About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder. The remaining 10% to 30% of patients have a family history of CRC that suggests a hereditary contribution, common exposures or shared risk factors among family members, or a combination of both.[
In addition, pathogenic variants in lower-penetrance genes may contribute to familial colon cancer risk. In such cases, gene-gene and gene-environment interactions may contribute to the development of CRC.
(Refer to the PDQ summaries on Colorectal Cancer Screening; Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment for more information about sporadic CRC.)
Colorectal Polyps as Precursors to Colorectal Cancer (CRC)
Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer, and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas).
Transformation of any polyp into cancer goes through the adenoma-carcinoma sequence. Polyps that have traditionally been considered nonneoplastic include those of the hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid types. However, in certain circumstances, hamartomatous and juvenile polyps can progress into cancer.
Research, however, does suggest a substantial risk of colon cancer in individuals with juvenile polyposis syndrome and Peutz-Jeghers syndrome, although the nonadenomatous polyps associated with these syndromes have historically been viewed as nonneoplastic.[
Epidemiological studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[
Two complementary interpretations of this observation are as follows:
More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. Adenocarcinomas are generally considered to arise from adenomas,[
The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[
In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[
Family History as a Risk Factor for CRC
Some of the earliest studies of family history of CRC were those of Utah families that reported a higher percentage of deaths from CRC (3.9%) among the first-degree relatives (FDRs) of patients who had died from CRC than among sex-matched and age-matched controls (1.2%).[
A systematic review and meta-analysis of familial CRC risk has been reported.[
The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one FDR with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years (RR, 3.87; 95% CI, 2.40–6.22) compared with family members of index cases diagnosed at ages 45 to 59 years (RR, 2.25; 95% CI, 1.85–2.72), and to family members of index cases diagnosed at age 60 years or older (RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in an FDR was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had an FDR with an adenoma.[
|Family History||Relative Risk of CRC[
||Absolute Risk (%) of CRC by Age 79 ya|
|CI = confidence interval; FDR = first-degree relative.|
|a Data from the Surveillance, Epidemiology, and End Results database.|
| b The absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRC[
|No family history||1||4a|
|One FDR with CRC||2.3 (95% CI, 2.0–2.5)||9b|
|More than one FDR with CRC||4.3 (95% CI, 3.0–6.1)||16b|
|One affected FDR diagnosed with CRC before age 45 y||3.9 (95% CI, 2.4–6.2)||15b|
|One FDR with colorectal adenoma||2.0 (95% CI, 1.6–2.6)||8b|
When the family history includes two or more relatives with CRC, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history to determine the number of relatives affected, their relationship to each other, the age at which the CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Computer models are now available to estimate the probability of developing CRC.[
Figure 1 shows the proportion of CRC cases that arise in various family risk settings.[
Figure 1. The fractions of colon cancer cases that arise in various family risk settings. Reprinted from Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000), with permission from Elsevier.
Inheritance of CRC Predisposition
Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all pathogenic variants known to cause a predisposition to CRC are inherited in an autosomal dominant fashion.[
The two most common causes of hereditary CRC are FAP (including AFAP), due to germline pathogenic variants in the APC gene,[
Figure 2. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer, a young age at onset in some individuals, and incomplete penetrance. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure. Because the cancer risk is not 100%, individuals who have Lynch syndrome may not develop cancer, such as the mother of the female with colon cancer diagnosed at age 37 years in this pedigree (called incomplete penetrance).
Identification of Individuals at High Genetic Risk of CRC
Guidelines have been developed by the American College of Medical Genetics and the National Society of Genetic Counselors to aid in the identification of patients appropriate for referral to a cancer genetic counseling service.[
When such persons are identified, options tailored to the patient situation are considered. (Refer to the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)
At this time, the use of pathogenic variant testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of pathogenic variants in CRC-associated genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost-effective.
Rather detailed recommendations for surveillance in FAP and Lynch syndrome have been provided by several organizations representing various medical specialties and societies. These organizations include the following:
The evidence bases for recommendations are generally included within the statements or guidelines. In many instances, these guidelines reflect expert opinion resting on studies that are rarely randomized prospective trials.
The epidemiology of CRC with regard to age at diagnosis is shifting, with individuals increasingly being diagnosed before age 50 years,[
In the absence of an additional family or personal history suggestive of Lynch syndrome, isolated cases of CRC diagnosed before age 36 years are uncommonly associated with MMR gene pathogenic variants. One study found MMR pathogenic variants in only 6.5% of such individuals,[
The use of polygenic risk scores (PRS) is being studied in the context of early-onset CRC in individuals who have tested negative for common CRC susceptibility variants (NCT02863107), with data from one large analysis [
Difficulties in Identifying a Family History of CRC Risk
The accuracy and completeness of family history data must be considered when using family history to assess individual risk in clinical practice and when identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[
Accuracy of patient-reported family history of colon cancer has been shown to be good, but it is not optimal. Patient report should be verified by obtaining medical records whenever possible, especially for reproductive tract cancers that may be relevant in identifying risk of Lynch syndrome and less reliably reported by some patients. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Several approaches are available to evaluate a patient with newly diagnosed CRC who may or may not be suspected of having a cancer genetics syndrome. The clinician may suspect a potential inherited disposition based on the family history and physical exam, and genetic tests are available to confirm these suspicions. The American College of Medical Genetics and Genomics has published guidelines for evaluating patients with suspected colon cancer susceptibility syndromes.[
A priori risk-assessment testing (which models risk based on a variety of factors, such as age at cancer onset and the spectrum of tumors in the family) may be an appropriate alternative in many cases. Application of such risk models does anticipate the use of multigene (panel) testing; however, their exact role remains to be established.
Molecular Events Associated With Colon Carcinogenesis
Much of our initial understanding of the molecular pathogenesis of CRC derived from rare hereditary CRC syndromes and revealed heterogeneity of CRC both molecularly and clinically. It is well accepted that most CRCs develop from adenomas. The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[
Chromosomal instability (CIN) pathway
The majority of CRCs develop through the CIN pathway. Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and frequent detectable losses at the molecular level of portions of chromosomes (loss of heterozygosity), such as 5q, 18q, and 17p; and pathogenic variants of the KRAS oncogene. The important genes involved in these chromosome losses are APC (5q), DCC/MADH2/MADH4 (18q), and TP53 (17p).[
Microsatellite instability (MSI) pathway
Soon thereafter, a subset (10%–15%) of CRCs was identified that lacked evidence of chromosomal instability but exhibited aberrations in microsatellite repeat sequences,[
The key characteristics of MSI cancers are that they have a largely intact chromosome complement and, as a result of defects in the DNA MMR system, more readily acquire pathogenic variants in important and often unique cancer-associated genes. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as DNA microsatellites.
The rate of adenoma-to-carcinoma progression appears to be faster in microsatellite-unstable tumors than in microsatellite-stable tumors.[
The knowledge derived from the study of inherited CRC syndromes has provided important clues regarding the molecular events that mediate tumor initiation and tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APC gene product.
CpG island methylator phenotype (CIMP) and the serrated polyposis pathway
Beginning in the 1980s, studies began reporting an increased risk of CRC in patients with hyperplastic polyposis syndrome (HPS), now referred to as serrated polyposis syndrome (SPS).[
Further histological characterization of serrated polyps led to subtypes: traditional serrated adenomas (TSA), mixed serrated polyps (MP), and more recently, sessile serrated adenoma/sessile serrated polyp (SSA/SSP).[
In colonoscopy screening studies, large serrated polyps were strongly and independently associated with the development of advanced colorectal neoplasms, while left-sided HPs were not. The term SSA has been a concern to clinicians as these characteristically lack nuclear atypia, the traditional hallmark of adenomas, but rather are termed adenomas due to other architectural features. The classification of SSA is supported by the knowledge that the molecular characteristics denote an increased cancer risk.[
While APs in Lynch syndrome patients can exhibit MSI, sporadic adenomas rarely do. However, serrated polyps with dysplasia can exhibit MSI with hypermethylation of the MLH1 promoter. Large (>1 cm) serrated polyps carry greater cancer risk than do conventional hyperplastic polyps and, when developing into cancers, characteristically exhibit MSI.[
The MSI seen in sporadic CRCs is due to hypermethylation of the promoter of MLH1, which abrogates its expression. As promoter regions of other tumor suppressor genes were "silenced" through hypermethylation, cancer genome studies of CRC ensued. These showed a consistent pattern of hypermethylation in the evaluated genes in approximately 50% of CRCs.[
CIMP-high CRCs were much more likely (82.1%; P < .0001) to express MSI than were microsatellite-stable CRCs (24.4%; P < .0001).[
Studies of polyps revealed CIMP-positive polyps in HPS patients and most frequently in right-sided SSAs.[
The characterization of CIMP CRCs and evidence that MSI occurs later in the adenoma-carcinoma sequence leads to modification of the previous colorectal tumorigenesis model, which was comprised of two pathways: MSI (MIN) and CIN. There is much overlap between the MSI and CIMP pathways. At the heart of the CIMP pathway are serrated polyps harboring BRAF pathogenic variants. The CIN pathway is characterized by AP precursors of which the vast majority harbor APC pathogenic variants that occur early in the pathway.
Major genes are defined as those that are necessary and sufficient for disease causation, with important pathogenic variants (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic variants in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[
The functions of the major colorectal (CRC) cancer genes have been reasonably well characterized over the past decade.[
|Gene||Syndrome||Hereditary Pattern||Predominant Cancers|
|FAP = familial adenomatous polyposis; JPS = juvenile polyposis syndrome; PJS = Peutz-Jeghers syndrome; PPAP = polymerase proofreading–associated polyposis.|
|APC||FAP, AFAP||Dominant||Colorectal, small bowel, gastric, etc.|
|TP53(p53)||Li-Fraumeni||Dominant||Multiple (including colorectal)|
|STK11(LKB1)||PJS||Dominant||Multiple (including colorectal, small bowel, pancreas)|
|PTEN||Cowden||Dominant||Multiple (including colorectal)|
|BMPR1A,SMAD4(MADH/DPC4)||JPS||Dominant||Gastric and colorectal|
|MLH1,MSH2,MSH6,PMS2,EPCAM||Lynch syndrome||Dominant||Multiple (including colorectal, endometrial, and others)|
De Novo Pathogenic Variant Rate
Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, FAP, JPS, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome are all thought to have high rates of spontaneous pathogenic variants, in the 25% to 30% range,[
Genetic Polymorphisms and CRC Risk
It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes.[
Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome or FAP. However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide variants (SNVs).
Several genome-wide association studies (GWAS) have been conducted with relatively large, unselected series of patients with CRC, who have been evaluated for patterns of polymorphisms in candidate and anonymous genes throughout the genome.[
Polygenic risk scores for colorectal cancer
There is increasing interest in using SNVs to expand germline risk assessment from monogenic high-/moderate-penetrance forms of CRC predisposition to polygenic forms of CRC risk assessment that may have broader applicability to the general population. To that end, multiple studies have examined the utility of polygenic risk scores (PRSs) to personalize CRC risk assessment in individuals otherwise considered to be at average risk for CRC.
One study examined 36 different SNVs previously linked to CRC susceptibility by GWAS in 341 men with CRC and 329 controls from a population-based registry of Japanese individuals. Investigators ultimately identified six of these SNVs to be associated with CRC risk in this population and constructed a PRS, which had reasonable discriminatory capacity (area under the curve [AUC], 0.63) for assessing a 10-year absolute risk of CRC. The investigators found that the performance of the PRS was marginally superior to a previously validated nongenetic risk prediction score (AUC, 0.60) incorporating age, body mass index, and tobacco and alcohol use, and found that a combined model including both SNV data and these nongenetic factors had superior discriminatory capacity for assessing a 10-year absolute CRC risk (AUC, 0.66).[
Another study analyzed a 95-SNV PRS in 108,062 individuals from three large consortia. Subsequent validation in 72,573 individuals found that the PRS was significantly associated with both early-onset (age, <50 y) and late-onset (age, ≥50 y) CRC.[
Despite such promising data, however, it is important to emphasize that such PRSs are not currently used in routine clinical settings and are not currently considered to be clinically actionable. Formal implementation studies examining the use of such PRSs to guide CRC risk assessment and screening in routine clinical care are warranted, on the basis of these encouraging data.
The APC I1307K polymorphism deserves special mention, given that it is commonly identified in individuals of Ashkenazi Jewish ancestry undergoing multigene (panel) testing [
Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient and family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch syndrome, Peutz-Jeghers syndrome [PJS], Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first four, while hamartomas were found to be characteristic in the last three.
With the development of the Human Genome Project and the identification in 1990 of the adenomatous polyposis coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by pathogenic variants in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations due to an APC pathogenic variant at the 3' or 5' ends of the gene. MUTYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the pathogenic variants were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for carriers of pathogenic variants (refer to Table 3).
|Syndrome||Absolute Risk of CRC in Carriers of a Pathogenic Variant|
|FAP = familial adenomatous polyposis; JPS = juvenile polyposis syndrome; PJS = Peutz-Jeghers syndrome.|
|a Cancer risk estimates quoted here predate the widespread use ofsurveillanceand prophylactic surgery.|
|FAP a||90% by age 45 y[
|Attenuated FAP||69% by age 80 y[
|Lynch syndrome||10% to 56% by age 75 y, depending on the gene involved[
|MUTYH-associated polyposis||35% to 53%[
|PJS||39% by age 70 y[
|JPS||17% to 68% by age 60 y[
With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for variants in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron -exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic variants from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance (VUS) that cannot be used for predictive purposes.
Familial Adenomatous Polyposis (FAP)
By 1900, several reports had demonstrated that patients with a large number of polyps (later subclassified as adenomas) were at very high risk of CRC and that the pattern of transmission in families was autosomal dominant. In the 20th century, the adenoma-to-carcinoma progression was confirmed, and FAP was recognized as the prototypical model for this progression.[
Figure 3. Familial adenomatous polyposis is characterized by multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life.
There is also a subset of classic FAP that has an attenuated phenotype. AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.)
FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[
In addition to a high risk of colon adenomas in FAP patients, various extracolonic manifestations have also been described, including upper gastrointestinal (GI) tract adenomas and adenocarcinomas; fundic gland stomach polyps; nonepithelial benign tumors (osteomas, epidermal cysts, dental abnormalities); desmoid tumors; congenital hypertrophy of retinal pigment epithelium (CHRPE); and malignant tumors (thyroid and brain tumors, hepatoblastoma). Refer to Table 4 for the risks of these extracolonic manifestations in FAP.
|Malignancy||Relative Risk||Absolute Lifetime Risk (%)|
|Adapted from Giardiello et al.,[
|a The Leeds Castle Polyposis Group.|
|Duodenal tumors and cancer||330.8||5.0–12.0|
|Gastric cancer||Not defined||0.6a|
FAP has also been known as familial polyposis coli or adenomatous polyposis coli (APC). Gardner syndrome was previously the diagnosis for FAP patients who manifested with colorectal polyposis, osteomas, and soft tissue tumors. However, Gardner syndrome has been shown genetically to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.[
Colon adenomas and CRC
Individuals who inherit a pathogenic variant in the APC gene have a very high likelihood of developing colonic adenomas; the risk has been estimated to be more than 90%.[
Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
CHRPE are flat, darkly pigmented lesions in the retina that are present in approximately 75% of patients with FAP [
Desmoid tumors are proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening.[
Most studies have found that 10% of FAP patients develop desmoids, with reported ranges of 8% to 38%. The incidence varies with the means of ascertainment and the location of the pathogenic variant in the APC gene.[
A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors.[
The natural history of desmoids is variable. Some authors have proposed a model for desmoid tumor formation whereby abnormal fibroblast function leads to mesenteric, plaque-like desmoid precursor lesions, which in some cases occur before surgery and progress to mesenteric fibromatosis after surgical trauma, ultimately giving rise to desmoid tumors.[
The desmoids in FAP are often intra-abdominal, may present early, and can lead to intestinal obstruction or infarction and/or obstruction of the ureters.[
These data suggest that genetic testing could be of value in the medical management of patients with FAP and/or multiple desmoid tumors. Those with APC genotypes predisposing to desmoid formation (e.g., at the 3' end or codon 1445 of the APC gene) appear to be at high risk of developing desmoids after any surgery, including risk-reducing colectomy and surgical surveillance procedures such as laparoscopy.[
The most common FAP-related gastric polyps are fundic gland polyps (FGPs). FGPs are often diffuse and not amenable to endoscopic removal. The incidence of FGPs has been estimated to be as high as 60% in patients with FAP, compared with 0.8% to 1.9% in the general population.[
The hyperplastic surface epithelium is, by definition, nonneoplastic. Accordingly, FGPs have not been considered precancerous. However, case reports of stomach cancer appearing to arise from FGPs have led to a reexamination of this issue.[
Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs).[
Gastric adenomas also occur in patients with FAP. The incidence of gastric adenomas in Western patients is reported to be between 2% and 12%, whereas in Japan, incidence is reported to be between 39% and 50%.[
More recently, a rise in incidence of gastric adenocarcinoma was observed in a Western FAP database.[
Duodenum/small bowel tumors
Whereas the incidence of duodenal adenomas is only 0.4% in unselected patients undergoing upper GI endoscopy,[
A retrospective review of FAP patients suggested that the adenoma-carcinoma sequence occurred in a temporal fashion for periampullary adenocarcinomas with a diagnosis of adenoma at a mean age of 39 years, high-grade dysplasia at a mean age of 47 years, and adenocarcinoma at a mean age of 54 years.[
FAP patients with particularly severe duodenal polyposis, sometimes called dense polyposis, or with histologically advanced duodenal adenomas appear to be at the highest risk of developing duodenal adenocarcinoma.[
The predictive utility of the Spigelman classification has been called into question. The point system for dysplasia classifies dysplasia as mild, moderate, or severe, yet pathologists do not customarily attempt to distinguish moderate dysplasia from low-grade. There are no studies validating interobserver concordance in classifying a villous component or interpretation of the degree of dysplasia. A study from the Cleveland Clinic comparing Spigelman classification and its components in patients with FAP with and without cancer found neither adenoma count nor villous component to be predictive of cancer risk.[
|Points||Polyp Number||Polyp Size (mm)||Histology||Dysplasia|
|Stage I, 1–4 points; Stage II, 5–6 points; Stage III, 7–8 points; Stage IV, 9–12 points.[
Other extracolonic tumors arising in FAP patients include papillary thyroid cancer, adrenal tumors, hepatoblastoma, and brain tumors.
Papillary thyroid cancer (cribriform morular type) has been reported to affect 1% to 2% of patients with FAP.[
Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH at the APClocus in an adrenocortical carcinoma (ACC) in an FAP patient.[
Hepatoblastoma is a rare, rapidly progressive, and usually fatal childhood malignancy that, if confined to the liver, can be cured by radical surgical resection. Multiple cases of hepatoblastoma have been described in children with an APC pathogenic variant.[
The constellation of CRC and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with pathogenic variants in APC (thus representing FAP), while colon cancer and glioblastoma are associated with pathogenic variants in mismatch repair (MMR) genes (thus representing Lynch syndrome).[
Medulloblastoma, a highly malignant embryonal central nervous system tumor, accounts for approximately 80% of the brain tumors found in FAP and primarily occurs in children with 70% diagnosed before age 16 years. High-grade astrocytomas and ependymomas have also been described in FAP patients. Although the relative lifetime risk of any brain tumor among members of an FAP family is increased 7-fold and that of medulloblastoma 90-fold, the absolute lifetime risk of any brain tumor is approximately 1% to 2%.[
Genetics of FAP
The adenomatous polyposis coli (APC) gene
The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; the main function of the APC protein is to regulate intracellular concentrations of beta-catenin, a major mediator of the Wnt signal transduction pathway. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. FAP and AFAP can be diagnosed genetically by testing for germline pathogenic variants in the APC gene in DNA from peripheral blood leukocytes. More than 300 different disease-associated pathogenic variants of the APC gene have been reported.[
Most APC pathogenic variants that occur between codon 169 and codon 1249 result in the classic FAP phenotype.[
A low-penetrance APC variant, I1307K, has been studied for its association with CRC. (Refer to the APC I1307K section in the Colorectal Cancer Susceptibility Genes section of this summary for more information.)
Genetic testing for FAP
Individuals who present with a classic FAP phenotype are candidates for APC testing. However, in many probands with a personal or family history of polyposis, multigene panel testing is an appropriate option to consider given the genetic heterogeneity of polyposis conditions and the phenotypic overlap among associated syndromes.
In particular, patients who develop fewer than 100 colorectal adenomatous polyps may pose a diagnostic challenge. The differential diagnosis includes AFAP, MAP, polymerase proofreading–associated polyposis (PPAP), and biallelic mismatch repair deficiency (BMMRD).[
For example, in a large cross-sectional study, pathogenic variants in APC were found in 80% (95% confidence interval [CI], 71%–87%) of individuals with more than 1,000 adenomas, 56% (95% CI, 54%–59%) in those with 100 to 999 adenomas, 10% (95% CI, 9%–11%) in those with 20 to 99 adenomas, and 5% (95% CI, 4%–7%) in those with 10 to 19 adenomas.[
Most commercial laboratories perform not only full gene sequencing but also deletion/duplication analysis of the APC and other genes. However, it is important to verify the testing methodology with each laboratory. Deletion analysis is especially important for individuals with FAP because 8% to 12% of affected individuals have a whole exon deletion or promoter 1B deletion in the APC gene, which would not be detected with sequencing.[
In families in which a pathogenic variant in the APC gene is identified, predictive testing for at-risk relatives can definitively identify or rule out the variant. Such testing is important to determine whether at-risk relatives need to undergo aggressive screening or whether such procedures are not necessary or can be discontinued (i.e., in relatives who test negative for the familial pathogenic variant).
Most patients with FAP have an affected parent, and a pattern of autosomal dominant inheritance may be observed in the family. Accordingly, cascade genetic counseling and testing may then be extended to at-risk family members. However, it is estimated that 25% of patients with FAP have a de novo pathogenic variant in APC, meaning that the variant does not appear to be inherited from either parent.[
The early appearance of FAP clinical features and the subsequent recommendations for surveillance beginning at puberty raise special considerations relating to the genetic testing of minors.[
Interventions for FAP
Individuals at risk of FAP, because of a known APC pathogenic variant in either the family or themselves, are evaluated for onset of polyposis by flexible sigmoidoscopy or colonoscopy. Once an FAP family member is found to manifest polyps, the only effective management to prevent CRC is colectomy. Prophylactic surgery has been shown to improve survival in patients with FAP.[
A Finnish nationwide, population-based, retrospective study evaluating whether surveillance of family members with FAP reduced overall mortality and improved survival demonstrated that family members of probands who were recruited to the screening program had equivalent survival to the general population up to 20 years after diagnosis of FAP.[
Endoscopic surveillance usually begins early (age, 10–15 y).[
Colon adenomas will develop in nearly 100% of individuals who are APC pathogenic variant–positive; risk-reducing surgery comprises the standard of care to prevent CRC after polyps have appeared and are too numerous or histologically advanced to monitor safely using endoscopic resection.
FAP patients and their doctors should have an individualized discussion to decide when surgery will be performed. It is useful to incorporate into the discussion the risk of developing desmoid tumors after surgery, as well as fecundity for women. Timing of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology.[
Surgical options include restorative proctocolectomy with ileal pouch anal anastomosis (IPAA), total colectomy with ileorectal anastomosis (IRA), or total proctocolectomy with ileostomy (TPC). TPC is reserved for patients with low rectal cancer in which the sphincter cannot be spared or for patients on whom an IPAA cannot be performed because of technical problems. There is no risk of developing rectal cancer after TPC because the whole mucosa at risk is removed. These procedures can be performed utilizing minimally invasive techniques.
Irrespective of whether a colectomy and an IRA or a restorative proctocolectomy is performed, most experts suggest that periodic and lifelong surveillance of the rectum or the ileal pouch be performed to remove or ablate any polyps. In earlier unselected studies, the risk of rectal cancer after total colectomy 20 years after IRA was reported to be as high as 25%.[
In most cases, the clinical polyp burden in the rectum at the time of surgery dictates the type of surgical intervention, namely, restorative proctocolectomy with IPAA versus IRA. Patients with a mild phenotype (<1,000 colonic adenomas) and fewer than 20 rectal polyps may be candidates for IRA at the time of prophylactic surgery.[
In patients who have undergone IPAA, it is important to continue annual surveillance of the ileal pouch because the cumulative risk of developing adenomas in the pouch has been reported to be up to 75% at 15 years.[
Celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, and nonspecific COX-2 inhibitors, such as sulindac (a nonsteroidal anti-inflammatory drug [NSAID]), have been associated with a decrease in polyp size and number in FAP patients, suggesting a role for chemopreventive agents in the treatment of this disorder.[
A small, randomized, placebo-controlled, dose-escalation trial of celecoxib in a pediatric population (aged 10–14 y) demonstrated the safety of celecoxib at all dosing levels when administered over a 3-month period.[
Omega-3-polyunsaturated fatty acid eicosapentaenoic acid in the free fatty acid form has been shown to reduce rectal polyp number and size in a small study of patients with FAP after subtotal colectomy.[
It is unclear at present how to incorporate COX-2 inhibitors into the management of FAP patients who have not yet undergone risk-reducing surgery. A double-blind placebo-controlled trial of 41 child and young adult carriers of APC pathogenic variants who had not yet manifested polyposis demonstrated that sulindac may not be effective as a primary treatment in FAP. There were no statistically significant differences between the sulindac and placebo groups over 4 years of treatment in incidence, number, or size of polyps.[
Consistent with the effects of COX-2 inhibitors on colonic polyps, in a randomized, prospective, double-blind, placebo-controlled trial, celecoxib reduced, but did not eliminate, the number of duodenal polyps in 32 patients with FAP after a 6-month course of treatment. Of importance, a statistically significant effect was seen only in individuals who had more than 5% of the duodenum involved with polyps at baseline and with an oral dose of 400 mg, given twice daily.[
Because of the common clustering of adenomatous polyps around the duodenal papilla (where bile enters the intestine) and preclinical data suggesting that ursodeoxycholate inhibits intestinal adenomas in mice that harbor an Apc germline variant,[
Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[
Level of evidence (celecoxib): 1b
One cohort study has demonstrated regression of colonic and rectal adenomas with sulindac treatment in FAP. The reported outcome of this trial was the number and size of polyps, a surrogate for the clinical outcome of main interest, CRC incidence.[
Level of evidence (sulindac): 1b
Preclinical studies of a small-molecule epidermal growth factor receptor (EGFR) inhibitor and low-dose sulindac in the Apcmin/+ mouse diminished intestinal adenoma development by 87% [
On the basis of the previously modest effects of sulindac and celecoxib on duodenal polyps in patients with FAP [
Level of evidence (sulindac + erlotinib): 1b
Management of extracolonic tumors
Patients who carry APC germline pathogenic variants are at increased risk of other types of malignancies, including desmoid tumors, gastric tumors, duodenal cancer, small bowel cancer, hepatoblastoma, thyroid cancer, and brain tumors. The management of these extracolonic tumors is described below.
The management of desmoids in FAP can be challenging and can complicate prevention efforts. There is no accepted standard treatment for desmoid tumors. Multiple medical treatments have generally been unsuccessful in the management of desmoids. Treatments have included antiestrogens, NSAIDs, chemotherapy, and radiation therapy, among others. Studies have evaluated the use of raloxifene alone, tamoxifen or raloxifene combined with sulindac, and pirfenidone alone.[
Thirteen patients with intra-abdominal desmoids and/or unfavorable response to other medical treatments who had expression of estrogen-alpha receptors in their desmoid tissues were included in a prospective study of raloxifene, given in doses of 120 mg daily.[
A second study of 13 patients with FAP-associated desmoid tumors, who were treated with tamoxifen 120 mg/day or raloxifene 120 mg/day in combination with sulindac 300 mg/day, reported that ten patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that three patients had stable disease for more than 30 months.[
A third study reported mixed results in 14 patients with FAP-associated desmoid tumors treated with pirfenidone for 2 years.[
There are reports of using imatinib mesylate to treat desmoid tumors in FAP patients with some success.[
Level of evidence: 4
The benefit of the tyrosine kinase inhibitor sorafenib in the treatment of desmoid tumors was demonstrated in a phase III randomized trial comparing sorafenib (400 mg daily) with placebo in 87 patients with unresectable progressive or symptomatic desmoid tumors.[
Level of evidence: 1
Because of the high rates of morbidity and recurrence, in general, surgical resection is not recommended in the treatment of intra-abdominal desmoid tumors. A review of experiences at one hospital suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.[
It is not clear what should be done with gastric adenomas. Only retrospective case series are available and point to a relatively low prevalence of gastric adenocarcinoma development in FAP patients.[
Level of evidence: 5
Duodenum/small bowel tumors
A baseline upper endoscopy, including side-viewing duodenoscopy, is typically performed between ages 25 and 30 years in FAP patients.[
The main advantages of the Spigelman classification are its long-standing familiarity to and usage by those in the field, which allows reasonable standardization of outcome comparisons across studies.[
|Spigelman Stage||NCCN (2020)[
|ESMO = European Society of Medical Oncology; NCCN = National Comprehensive Cancer Network.|
|See belowfor additional information about the use of surgical resection in Spigelman stage IV disease.|
|0 (no polyps)||Endoscopy every 4 y||Not specified|
|I||Endoscopy every 2–3 y||Endoscopy every 5 y|
|II||Endoscopy every 1–3 y||Endoscopy every 3 y|
|III||Endoscopy every 6–12 mo||Endoscopy every 1–2 y|
|IV||Surgical evaluation||Endoscopy every 6-12 mo|
|Complete mucosectomy or duodenectomy, or Whipple procedure if duodenal papilla is involved|
|Expert endoscopic surveillance every 3–6 mo||Surgical options include duodenotomy with polypectomy, pancreas-sparing duodenectomy and pancreaticoduodenectomy (Whipple procedure)|
The results of long-term duodenal adenoma surveillance of FAP patients in Nordic countries and the Netherlands revealed significant duodenal cancer risk in FAP patients.[
Level of evidence (screening for duodenum/small bowel tumors): 3
Many factors, including severity of polyposis, comorbidities, patient preferences, and availability of adequately trained physicians, determine whether surgical or endoscopic therapy is selected for polyp management. Endoscopic resection or ablation of large or histologically advanced adenomas appears to be safe and effective in reducing the short-term risk of developing duodenal adenocarcinoma;[
The endoscopic approach to larger and/or flatter adenomas of the duodenum depends on whether the ampulla is involved. Endoscopic mucosal resection (EMR) after submucosal injection of saline, with or without epinephrine and/or dye, such as indigo carmine, can be employed for nonampullary lesions. Ampullary lesions require even greater care including endoscopic ultrasound evaluation for evidence of bile or pancreatic duct involvement. Stenting of the pancreatic duct is commonly performed to prevent stricturing and pancreatitis. The stents require endoscopic removal at an interval of 1 to 4 weeks. Because the ampulla is tethered at the ductal orifices, it typically does not uniformly lift with injection, so injection is commonly not used. Any consideration of EMR or ampullectomy requires great experience and judgment, with careful consideration of the natural history of untreated lesions and an appreciation of the high rate of adenoma recurrence despite aggressive endoscopic intervention.[
Reluctance to consider surgical resection is related to the short-term morbidity and mortality and the long-term complications related to surgery. Although these concerns are likely overstated,[
Level of evidence (treatment of duodenum/small bowel tumors): 4
Although level 1 evidence is lacking, a consensus opinion recommends a baseline thyroid examination beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP, with a repeat ultrasound every 2 to 5 years if results are normal.[
Level of evidence (thyroid cancer ultrasound screening): 4
Although level 1 evidence is lacking, a consensus panel has suggested that liver palpation, abdominal ultrasonography, and measurement of serum alpha-fetoprotein every 3 to 6 months for the first 5 years of life in children with a predisposition to FAP be considered.[
Level of evidence (hepatoblastoma or adrenal cancer screening): 5
Medulloblastoma is a highly malignant tumor that is usually only symptomatic 6 months or less before diagnosis; annual surveillance of asymptomatic patients may be insufficient. Thus, surveillance by means of regular CT or magnetic resonance imaging cannot be advocated. FAP family members who do not yet have polyposis but have signs or symptoms suggestive of a brain tumor should be evaluated with neuroimaging because brain tumors present before polyposis in more than half of FAP patients. Careful evaluation is also important among FAP families in which one member already has a brain tumor because familial clustering occurs. Of such families with FAP-associated brain tumors, 40% had two affected members.[
Attenuated Familial Adenomatous Polyposis (AFAP)
AFAP was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, although they ranged in number from a few to hundreds.[
Genetics of AFAP
AFAP is associated with particular subsets of APC pathogenic variants. Three groups of site-specific APC pathogenic variants causing AFAP have been characterized:[
In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), Lynch syndrome, BMMRD, germline variants in the DNA polymerase proofreading subunits (POLD1 or POLE), or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or Lynch syndrome.
APC testing is an important component of the evaluation of patients suspected of having AFAP.[
Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[
Table 7 summarizes the clinical practice guidelines from different professional societies regarding surveillance of AFAP.
|Organization||Condition||Screening Method||Screening Frequency||Age Screening Initiated||Comment|
|IPAA = ileal pouch–anal anastomosis; IRA = ileorectal anastomosis; NCCN = National Comprehensive Cancer Network.|
|a Fewer than 20 adenomas that are each <1 cm in diameter and without advanced histology so that colonoscopy with polypectomy can be used to effectively eliminate the polyps.|
|Europe Mallorca Group (2008)[
||AFAP||Colonoscopy||Every 2 y; every 1 y if adenomas are detected||18–20 y|
||Personal history of AFAP with small adenoma burdena||Colonoscopy||Every 1–2 y||If patient had colectomy with IRA, endoscopic evaluation every 6–12 mo depending on polyp burden|
|Chemoprevention may be considered to facilitate management of the remaining rectum or pouch post surgery in select patients with progressive polyp burden|
||Personal history of AFAP with adenoma burden that cannot be handled endoscopically||Not applicable||Not applicable||Not applicable||Colectomy with IRA preferred. Consider proctocolectomy with IPAA if patient has dense rectal polyposis|
||Asymptomatic at-risk family member; family pathogenic variant known;APCpathogenic variant status unknown or positive||Colonoscopy||Every 1–2 y ifAPCpositive; every 2 y if unknown||Late teens||IfAPCpathogenic variant status not tested, discuss advantages of genetic testing|
MUTYH-Associated Polyposis (MAP)
MAP is an autosomal recessively inherited polyposis syndrome caused by pathogenic variants in the Mut Y homolog gene. The Mut Y homolog gene, which is known as MUTYH, was initially called MYH, but was subsequently corrected because the myosin heavy chain gene already had that designation. MUTYH is located on chromosome 1p34.3-32.1.[
The MUTYH gene was first linked to polyposis in 2002 in three siblings with multiple colonic adenomas and CRC but no APC pathogenic variant.[
Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients.[
Although MAP is the only known biallelic (recessive) adenoma cancer predisposition syndrome described to date, there are examples of biallelic cases presenting with childhood tumors in which MMR genes are involved. (Refer to the Biallelic mismatch repair deficiency section in the Lynch syndrome section of this summary for more information.)
Table 8 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.
|Organization||Condition||Screening Method||Screening Frequency||Age Screening Initiated||Comment|
|CRC = colorectal cancer; FDR = first-degree relative; IPAA = ileal pouch–anal anastomosis; IRA = ileorectal anastomosis; NCCN = National Comprehensive Cancer Network; SDR = second-degree relative.|
|a Fewer than 20 adenomas that are each <1 cm in diameter and without advanced histology so that colonoscopy with polypectomy can be used to effectively eliminate the polyps.|
|Europe Mallorca Group (2008)[
||Carrier ofMUTYHpathogenic variants||Colonoscopy||Every 2 y||18–20 y|
|Nieuwenhuis et al. (2012)[
||Carrier ofMUTYHpathogenic variants||Colonoscopy||Every 1–2 y|
||Personal history of MAP, small adenoma burdena||Colonoscopy||Every 1–2 y||If patient had colectomy with IRA, endoscopic evaluation every 6–12 mo depending on polyp burden|
|Chemoprevention may be considered to facilitate management of the remaining rectum or pouch post surgery in select patients with progressive polyp burden|
||Personal history of MAP with adenoma burden that cannot be handled endoscopically||Not applicable||Not applicable||Not applicable||Colectomy with IRA preferred. Consider proctocolectomy with IPAA if patient has dense rectal polyposis. If patient had colectomy with IRA, then endoscopic evaluation of rectum every 6–12 mo depending on polyp burden|
||Asymptomatic, at-risk family member; family pathogenic variant known;MUTYHpathogenic variant status unknown or positive (biallelic)||Colonoscopy||Every 1–2 y||25–30 y||If positive for a singleMUTYHpathogenic variant, colonoscopy every 5 y beginning at age 40 y or 10 y before anFDR's CRC diagnosis, if applicable. Evidence is needed to inform screening recommendations for the following situations: the presence of aMUTYHvariant and anSDRwith CRC and a monoallelicMUTYHcarrier unaffected by CRC with no family history of CRC|
Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, thyroid, and skin cancers (melanoma, squamous epithelial, and basal cell carcinomas).[
Duodenal polyps in MAP
Similar to FAP, individuals with MAP often develop duodenal adenomas, and are at risk of developing duodenal cancer. Given the relatively recent identification of MAP compared with FAP, the incidence of duodenal polyps and risk of duodenal cancer in MAP is less well defined. Small case series have suggested the incidence of duodenal polyps in MAP to be approximately 30%, considerably lower than that of FAP. In a registry-based study the prevalence of duodenal polyps was 17%; however, only 50% of individuals in this study had undergone an upper GI endoscopy, suggesting the incidence of duodenal polyps was likely underestimated. The lifetime risk of duodenal cancer was estimated to be 4%.[
A registry study from the United Kingdom and the Netherlands explored incidence of duodenal polyps and duodenal cancer in a group of patients with MAP who were undergoing regular duodenal surveillance.[
Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying biallelic MUTYH pathogenic variants and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.
The clinical phenotype of monoallelic MUTYH pathogenic variants is less well characterized with respect to incidence and associated clinical phenotypes, and its role in susceptibility to polyposis and colorectal carcinoma remains unclear. Approximately 1% to 2% of the general population carry a pathogenic variant in MUTYH.[
MMR genes may interact with MUTYH and increase the risk of CRC. An association between MUTYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 pathogenic variants in carriers of monoallelic MUTYH pathogenic variants with CRC compared with noncarriers with CRC (11.5% vs. 0%; P = .037).[
Oligopolyposis is a popular term used to describe the clinical presentation of a polyp count or burden that is greater than anticipated in the course of screening in average-risk patients but that falls short of the requirement for a diagnosis of FAP. Thus, oligo-, Greek for few, can mean different things to different observers. While conceding a lack of consensus on the matter, the National Comprehensive Cancer Network (NCCN) committee on CRC screening suggests an AFAP diagnosis is worth considering when a lifetime aggregate of 10 to 99 adenomas are present. The term oligopolyposis will be used here to describe the circumstance in which the polyp count (generally adenoma) is large enough, with or without any attendant family history, to raise in the mind of the endoscopist the possibility of an inherited susceptibility.
A majority of patients with oligopolyposis involving adenomas are not found to have an underlying predisposition when evaluated for pathogenic variants in known predisposition genes. Such cases are generally managed as if they are at an increased risk of recurrent adenomas even when the colon can be cleared of polyps endoscopically.
AFAP resulting from pathogenic germline APC variants may be the most common cause of oligopolyposis where a specific causative germline alteration cancer has been identified. Some AFAP cases with oligopolyposis will eventually develop more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC pathogenic variant are clearly variant cases of FAP, as the term AFAP implies.[
Pathogenic variants in related DNA polymerase genes POLE and POLD1 have been described in families with oligopolyposis, CRC, and endometrial cancer, and this condition has come to be known as polymerase proofreading–associated polyposis (PPAP).[
A similar approach, whole-genome testing for shared variants, with further "filtering" by linkage analysis identified a variant in the POLD1 gene (p.Ser478Asn; c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to variants related to base substitution. A subsequent study confirmed that POLE pathogenic variants are a rare cause of oligopolyposis and early-onset CRC.[
A study utilizing whole-exome sequencing in 51 individuals with multiple colonic adenomas from 48 families identified a homozygous germline nonsense pathogenic variant in seven affected individuals from three unrelated families in the base-excision repair gene NTHL1.[
Hereditary mixed polyposis, characterized by histology that often includes adenomatous and hyperplastic polyps, has been associated with GREM1 pathogenic variants in a small number of Ashkenazi Jewish families. Polyp number in this syndrome is highly variable but is often in the spectrum consistent with oligopolyposis. (Refer to the Hereditary mixed polyposis syndrome [HMPS] section of this summary for more information.)
NTHL1, POLE, POLD1, and GREM1 pathogenic variant testing is being incorporated into the multigene (panel) tests for CRC susceptibility offered commercially along with APC and MUTYH so that a polyposis panel can be ordered up front for the patients with oligopolyposis. There are minimal data on the optimal surveillance approach for individuals found to have pathogenic germline variants in NTHL1 (biallelic carriers only), POLE, or POLD1, although it is presumed that the risk of CRC is comparable to what is seen in Lynch syndrome, and some guidelines are endorsing similarly early and frequent colonoscopic screening.
Oligopolyposis caused by other polyposis histologies can be distinguished from adenomatous polyposis on simple endoscopic and histologic grounds. For example, individuals with juvenile polyposis syndrome (JPS), PJS, or PTEN hamartoma tumor syndrome (Cowden syndrome) can all manifest oligopolyposis, often inclusive of hamartomatous polyps, as well as other more common polyp histologies (e.g., adenomas).
Serrated polyposis can likewise present in highly variable fashion. The World Health Organization (WHO) criteria for serrated polyposis (≥5 serrated polyps proximal to sigmoid with 2 polyps ≥1 cm, or any number of polyps proximal to sigmoid if there is a relative with serrated polyposis, or ≥20 serrated polyps anywhere in the colon) have never been validated. Rarely, families with serrated polyposis can be identified to harbor pathogenic germline RNF43 variants, but most cases of serrated polyposis cannot be linked to an underlying genetic basis.[
Two very small case series have described oligopolyposis with varying polyp histologies (e.g., adenomas, serrated, inflammatory, and hamartomatous polyps) in individuals previously treated with chemotherapy and radiation therapy for a prior childhood malignancy.[
Lynch syndrome is the most common inherited CRC syndrome and accounts for approximately 3% of all newly diagnosed cases of CRC. It is an autosomal dominant condition caused by pathogenic variants in the MMR genes MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6), and PMS2 (postmeiotic segregation 2), as well as the gene EPCAM (epithelial cellular adhesion molecule, formerly known as TACSTD1), in which deletions in EPCAM cause epigenetic silencing of MSH2. Lynch syndrome is also associated with a predisposition for developing several extracolonic manifestations, including sebaceous adenomas and cancers of the endometrium and ovaries, stomach, small intestine, transitional cell carcinoma of the ureters and renal pelvis, hepatobiliary system, pancreas, and brain. Lynch syndrome–associated cancers exhibit MSI; therefore, tumor testing is a key component in the diagnosis of Lynch syndrome, in addition to family history. Universal tumor testing of all CRCs is now recommended as a strategy to screen for Lynch syndrome and identify those individuals who may subsequently benefit from germline genetic testing. Intensive cancer screening and surveillance strategies, including frequent colonoscopy, along with risk-reducing surgeries, are mainstays in patients with Lynch syndrome.
History of Lynch syndrome
Between 1913 and 1993, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset of CRC; high risk of synchronous (and metachronous) colorectal tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as cancer family syndrome, and hereditary nonpolyposis colorectal cancer (HNPCC) were used to describe this entity.[
The term Lynch syndrome replaced HNPCC and is applied to cases in which the genetic basis can be confidently linked to a germline pathogenic variant in a DNA MMR gene. Moreover, HNPCC is misleading as many patients have polyps and many have tumors other than CRC.
With the increased recognition of families that were considered to have a genetic predisposition to the development of CRC, research for a causative etiology led to the development of the Amsterdam criteria in 1990.[
In 1987, a chromosomal deletion of a small segment of 5q led to the detection of a genetic linkage between FAP and this genomic region,[
In 2009, a germline deletion in the EPCAM gene was identified as another cause of MSH2 inactivation in the absence of a germline pathogenic variant in MSH2. The variant in EPCAM led to hypermethylation of the MSH2 promoter. Thus, EPCAM, which is not a DNA MMR gene, is also implicated in Lynch syndrome and is now routinely tested in at-risk patients along with the DNA MMR genes listed above.
Defining Lynch syndrome families
Families with a preponderance of CRC and a possible genetic predisposition were initially categorized as having Lynch syndrome based on family history criteria, as well as personal history of young-onset CRC. With the advent of molecular tumor diagnostic testing and the discovery of the germline alterations associated with Lynch syndrome, the clinical criteria have currently fallen out of favor due to their underperformance. However, their use, or the risk estimates provided by the Lynch syndrome prediction models, may be applicable among individuals without personal history of cancer but with a family history suggestive of Lynch syndrome, or for those individuals with CRC but without available tumor for molecular diagnostic testing. (Refer to the Universal tumor testing to screen for Lynch syndrome and the Clinical risk assessment models that predict the likelihood of an MMR gene pathogenic variant sections of this summary for more information.)
The first criteria for defining Lynch syndrome families were established by the International Collaborative Group meeting in Amsterdam in 1990 and are known as the Amsterdam criteria.[
Amsterdam criteria I (1990):
Amsterdam criteria II (1999):
These criteria were subsequently used beyond research purposes to identify potential candidates for microsatellite and germline testing. However, the Amsterdam criteria failed to identify a substantial proportion of Lynch syndrome kindreds; families that fulfilled Amsterdam criteria I but did not have evidence of MSI and were without a pathogenic germline variant in a DNA MMR gene, were referred to as familial colorectal cancer type X (FCCX). (Refer to the FCCX section of this summary for more information.)
With the hallmark feature of MSI associated with Lynch syndrome tumors, and the limitations of the Amsterdam criteria related to low sensitivity, the Bethesda guidelines were introduced in 1997. The Bethesda guidelines are a combination of clinical, histopathologic, and family cancer history features that identify cases of CRC that warrant MSI tumor screening. The Bethesda guidelines (with a subsequent revision in 2004) were formulated to target patients in whom evaluation of CRC tumors for MMR deficiency should be considered, and to improve the sensitivity of clinical criteria used to identify individuals who are candidates for mutational DNA analysis.[
Bethesda guidelines (1997):
Revised Bethesda guidelines (2004)*:
*One criterion must be met for the tumor to be considered for MSI testing.
**Lynch syndrome–associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[
Although the Bethesda guidelines were able to identify a higher proportion of Lynch syndrome carriers than the Amsterdam criteria, they still missed approximately 30% of Lynch syndrome families.[
With the advent of alternative approaches, including universal testing of all newly diagnosed cases of CRC for MSI (regardless of age at diagnosis or family history of cancer), clinical criteria for Lynch syndrome have been rendered obsolete. While the Bethesda guidelines were intended for individuals with cancer, their performance in individuals unaffected by cancer may still be of use. Given the limited modalities available to assess unaffected individuals for Lynch syndrome, family history and the use of clinical criteria may be appropriate in identifying those who warrant further genetic evaluation and testing.
Clinical risk assessment models that predict the likelihood of an MMR gene pathogenic variant
Because health care providers ineffectively use clinical criteria to select individuals with CRC for genetic referral and evaluation for Lynch syndrome, computer-based clinical prediction models were developed and introduced in 2006 as alternative modalities to provide systematic genetic risk assessment for Lynch syndrome. The risk models include the PREMM (PREdiction Model for gene Mutations) models, MMRpredict, and MMRpro.[
Three models (PREMM[1,2,6], MMRpredict, and MMRpro) quantify an individual's probability of carrying an MMR gene variant in MLH1, MSH2, and MSH6. The PREMM(1,2,6) model was subsequently extended to include prediction of pathogenic PMS2 and EPCAM variants and is the only model to provide prediction of all five genes associated with Lynch syndrome (PREMM5).[
While the models were all created for the same purpose, they differ in the way they were developed and the variables used to predict risk. In addition, the populations in which they were validated reveal each model's specific characteristics that may impact accuracy.[
Overall, there is ample evidence that each of the models has superior performance characteristics of sensitivity, specificity, and positive and negative predictive values that support their use when compared with the existing clinical guidelines for diagnosis and evaluation of Lynch syndrome. Because of the diverse clinical settings in which a health care provider has the opportunity to assess an individual for Lynch syndrome, prediction models offer a potentially feasible and useful strategy to systematically identify at-risk individuals, whether or not they are affected with CRC.
In conclusion, the presence of tumor MSI in CRCs, along with a compelling personal and family history of cancer, warrants germline genetic testing for Lynch syndrome, and most clinical practice guidelines provide for such an approach. These guidelines combine genetic counseling and testing strategies with clinical screening and treatment measures. Providers and patients alike can use these guidelines to better understand available options and key decisions. (Refer to Table 13 for more information about practice guidelines for diagnosis and colon surveillance in Lynch syndrome.)
Genetics of Lynch syndrome
The genetics of both the tumor and the germline have an important role in the development and diagnosis of Lynch syndrome. Tumor DNA in Lynch syndrome–associated tumors exhibits characteristic MSI, and in these cases, there is typically loss of IHC expression for one or more of the proteins associated with the MMR genes. Molecular testing with MSI and/or IHC has been adopted as a universal screen for diagnosis of Lynch syndrome in newly diagnosed patients with CRC and endometrial cancer. IHC testing results can potentially direct gene-specific germline testing. Many genetic testing laboratories offer multigene (panel) tests that simultaneously test for pathogenic variants in all of the Lynch syndrome–associated genes (and often additional genes associated with inherited cancer susceptibility).
Genetic and molecular testing for Lynch syndrome
The presence of MSI in colorectal tumor specimens is a hallmark feature of Lynch syndrome and can be cause for suspicion of a germline pathogenic MMR gene variant. Microsatellites are short, repetitive sequences of DNA (mononucleotides, dinucleotides, trinucleotides, or tetranucleotides) located throughout the genome, primarily in intronic or intergenic sequences.[
Certain histopathologic features are strongly suggestive of MSI phenotype, including the presence of tumor-infiltrating lymphocytes (refer to Figure 4), Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity.[
Figure 4. Tumor-infiltrating lymphocytes are a histopathologic feature suggestive of microsatellite instability.
Initial designation of a colorectal adenocarcinoma as microsatellite unstable was based on the detection of a specified percentage of unstable loci from a panel of three dinucleotide and two mononucleotide repeats that were selected at a National Institutes of Health (NIH) Consensus Conference and referred to as the Bethesda panel. If more than 30% of a tumor's markers were unstable, it was scored as MSI-H; if at least one, but fewer than 30% of markers were unstable, the tumor was designated MSI-low (MSI-L). If no loci were unstable, the tumor was designated microsatellite stable (MSS). Most tumors arising in the setting of Lynch syndrome will be MSI-H.[
The original Bethesda panel has been replaced by a pentaplex panel of five mononucleotide repeats,[
(Refer to the Prognostic and therapeutic implications of MSI section of this summary for more information about the treatment implications of MSI testing.)
(Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for information about the utilization of MSI status in the diagnostic workup of a patient with suspected Lynch syndrome.)
IHC methods are cheaper, easier to understand, and more widely available as a surrogate for MSI and, for these reasons, have replaced polymerase chain reaction (PCR)–based MSI testing in most institutions. IHC is performed in the colorectal or endometrial tumor (or metastatic sites) [
MSI can lead to nucleotide-pairing slippage (looping) in which single nucleotide mispairs are introduced. Heterodimers of MMR proteins are formed to identify the errors and bind the DNA at these sites.[
Figure 5. Immunohistochemical tumor testing for protein expression of the mismatch repair genes associated with Lynch syndrome, depicted for a single patient with colorectal cancer. Protein expression is preserved for MSH2 and MSH6 (inset) and absent for MLH1 and PMS2 (inset). Absence of MMR protein expression is suggestive of Lynch syndrome and warrants additional evaluation.
As a result, when the germline pathogenic variant is in the MSH2 gene, the tumor IHC may not express both MSH2 and MSH6, as the latter protein requires binding to MSH2 for stability. In this case, if no pathogenic variant is found in either gene, germline pathogenic variant testing for EPCAM should be considered if it was not already included. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 pathogenic variant identified will have germline deletions in EPCAM.[
In patients with no variants in any of these genes, tumor sequencing may reveal double somatic MSH2 mutations. (Refer to the EPCAM and Lynch-like or HNPCC-like syndrome sections of this summary for more information.)
Similarly, the loss of MLH1 (either by germline pathogenic variant or hypermethylation of the MLH1 promoter) results in the absence of expression of both MLH1 and PMS2 proteins in the tumor. The most common abnormal IHC pattern for DNA MMR proteins in colorectal adenocarcinomas is loss of expression of MLH1 and PMS2. PMS2 and MLH1 function as a stable heterodimer known as MutLα. MutLα binds to MutSβ and guides excision repair of the newly synthesized DNA strand.[
Unlike MLH1 and MSH2 (which both dimerize with other proteins or have other binding partners), germline pathogenic variants in MSH6 and PMS2 result in the isolated loss of those specific proteins by IHC. However, tumors from MSH6 pathogenic variant carriers may not display the MSI phenotype at a frequency as high as MLH1 and MSH2 carriers (despite an inactive DNA MMR system), as there are pathogenic missense variants that do not completely abrogate protein expression yielding false negative results by IHC testing.[
In some cases, tumors manifest MSI and/or IHC shows loss of DNA MMR protein expression, but no germline pathogenic variant is identified. This condition is known as Lynch-like (or HNPCC-like) syndrome and the tumor phenotype is predominantly due to biallelic somatic inactivation of DNA MMR genes and not a pathogenic germline alteration. (Refer to the Lynch syndrome–related syndromes section of this summary for more information.)
|Loss of Protein Expression||Germline MMR Defect Predicted by IHC Protein Expression Loss|
|IHC = immunohistochemistry; MMR = mismatch repair.|
It is important to recognize that hypermethylation of the MLH1 promoter, a somatic event confined to the tumor, can lead to abnormal protein expression of MLH1 on IHC. Approximately 10% to 15% of sporadic CRC cases have a microsatellite unstable tumor phenotype due to MLH1 hypermethylation and are not heritable. These sporadic MSI colon cancers [
BRAF pathogenic variants have been detected in 68% of CRC tumors with MLH1 promoter hypermethylation and very rarely, if ever, in CRC from patients with Lynch syndrome.[
Biallelic mismatch repair deficiency (BMMRD)
Rarely, patients with MMR gene variants carry such variants in both parental alleles. When two variant alleles are identified, whether homozygous or compound heterozygous, this is termed biallelic mismatch repair deficiency (BMMRD) or constitutional mismatch repair deficiency (CMMRD). The likelihood of BMMRD involving homozygous MMR gene pathogenic variants will inevitably be higher among consanguineous unions. Rates of consanguinity may be higher in rural and geographically and/or culturally isolated populations.[
Tumor studies yield characteristic abnormalities. In a series of 28 patients with BMMRD,[
The PMS2 gene is markedly overrepresented in cases of BMMRD. It has been suggested that the presence of homozygosity in other MMR gene variants is a prenatally lethal state, while milder expression of PMS2 variants is consistent with survival when present in both parental alleles.
(Refer to the BMMRD section in the Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome section for more information about the clinical phenotype of BMMRD.)
|Clinical Phenotype||Pathogenic Germline Variant in DNA MMR||Somatic Inactivation of DNA MMR||Tumor Phenotype|
|BMMRD = biallelic mismatch repair deficiency; FCCX = familial colorectal cancer type X; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stable.|
| a Adapted from Carethers et al.[
|Lynch syndrome||Present in one allele||Present in one allele||MSI|
|Sporadic CRC with hypermethylation ofMLH1promoter||Absent||+BRAF||MSI|
|BMMRD||Present in two alleles||Absent||MSI (tumor and normal tissue)|
|Lynch-like||Absent||Present in two alleles||MSI|
While somatic hypermethylation of the MLH1 promoter is acquired and not uncommon, examples of MLH1 promoter hypermethylation have been described in the germline and are generally not associated with a stable Mendelian inheritance. This constitutional methylation of MMR genes occurs most often in MLH1 and, to a lesser extent, MSH2 and is termed constitutional epimutation.[
Interpreting molecular alterations in tumors and distinguishing the likely primary epimutation cases from those of sporadic MSI poses significant challenges. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Rare instances of a de novo constitutional epimutation in MLH1[
Such MLH1-predominant primary epimutations are to be distinguished from secondary epimutations such as those occurring when MSH2 is methylated as a consequence of inherited variants in the upstream EPCAM gene. (Refer to the EPCAM section of this summary for more information.)
Molecular diagnostic tumor testing to screen for Lynch syndrome in clinical practice
While many molecular pathology laboratories can assess both MSI and IHC, an approach that uses IHC testing as the initial screen for defective MMR activity has been favored because it is less labor intensive and more cost-effective.[
Universal tumor testing to screen for Lynch syndrome
Use of MSI and/or IHC testing in all newly diagnosed cases of CRC, regardless of the age at diagnosis or family history of cancer, increases the sensitivity of the initial screen for Lynch syndrome, especially for carriers of MSH6 and PMS2 pathogenic variants. This approach is more sensitive than existing clinical criteria, as many individuals with Lynch syndrome are diagnosed at older ages (>50 y) and have less striking family histories of CRC than previously appreciated. This universal testing of colorectal (and endometrial) tumors using either MSI or IHC testing has been recommended by many professional organizations and is being widely adopted.[
Genetic risk assessment and MMR gene variant testing in individuals with newly diagnosed CRC can lead to improved outcomes for the patient and at-risk family members. Dating back to 2009, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC), reported that there was sufficient evidence to recommend offering tumor screening for Lynch syndrome to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives.[
Several studies have demonstrated the feasibility of universal screening for Lynch syndrome. Initial experience from one institution found that among 1,566 patients screened using MSI and IHC, 44 patients (2.8%) had Lynch syndrome. For each proband, an average of three additional family members were subsequently diagnosed with Lynch syndrome.[
The consideration to further stratify the recommendation for molecular tumor testing by age (i.e., 70 y) warrants attention as it influences the cost-effectiveness of universal screening strategy.
Loss of MLH1 and PMS2 due to somatic hypermethylation is not uncommon, and is more frequently detected with increasing age at CRC diagnosis.[
Screening individuals with CRC for Lynch syndrome is most often performed in a stepwise fashion based on IHC tumor testing results that evaluate protein expression for the four MMR genes related to Lynch syndrome. One proposed strategy is summarized in Figure 6. This framework does not incorporate a germline testing approach that simultaneously evaluates multiple cancer susceptibility genes (multigene [panel] testing), which may be useful in select patient populations. (Refer to the Multigene [panel] testing section of this summary for more information.)
Figure 6. A proposed strategy to evaluate individuals with colorectal cancer for Lynch syndrome based on immunohistochemical tumor testing results. Adapted from Geiersbach KB, Samowitz WS. Microsatellite instability and cancer. Arch Pathol Lab Med 135(10):1269-77, 2011.
Clinicians are increasingly utilizing tumor sequencing to advance therapeutic decisions in a more personalized approach, particularly in patients with metastatic disease. The performance of next-generation tumor sequencing (NGS) of CRCs for the detection of Lynch syndrome was compared with existing screening protocols that include MSI testing and IHC staining (with BRAF p.V600E testing) in 419 CRC cases recruited in a multicenter, population-based study.[
A 2019 retrospective study using data from a large, community-based, integrated U.S. health care system compared the diagnostic performance of age-restricted screening strategies for Lynch syndrome by reflex MMR IHC of all CRCs versus a universal screening strategy without an upper age limit.[
Cost-effectiveness of universal tumor screening for Lynch syndrome
Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify Lynch syndrome among individuals aged 70 years or younger with newly diagnosed CRC .[
NCCN 2020 guidelines support universal screening of all CRCs with IHC and/or MSI, and/or a comprehensive tumor NGS panel or germline multigene (panel) testing.[
However, it is important to note that the conclusions from this study were contingent upon the number of at-risk relatives who underwent germline testing (through a process known as cascade screening) based on the identification of a germline MMR gene variant in the index case of CRC in the family. In their model, to meet the accepted $50,000 cost-effective threshold, testing a minimum of three to four relatives was necessary.[
Another study addressed the cost-effectiveness of testing for pathogenic variants in the Lynch syndrome–associated genes and evaluated 21 screening strategies, including clinical criteria, use of clinical Lynch syndrome prediction models, and molecular tumor testing.[
Establishment of an upper age limit for universal tumor testing remains controversial. Some experts have endorsed testing only individuals with CRC who are younger than 70 years (reserving testing in individuals ≥70 y for only those meeting the revised Bethesda criteria; with this strategy, 5% of carriers would be missed).[
Another cost-effectiveness analysis was performed using data from 179 consecutive endometrial cancer patients diagnosed at or before age 70 years and screened with MMR IHC and reflex MLH1 promoter hypermethylation, among whom seven Lynch syndrome carriers (3.9%) were identified.[
The cost-effectiveness of universal tumor testing in both CRC and endometrial cancer is largely driven by the assumption of cascade screening through which other at-risk family members will be identified, tested, and subsequently pursue their own cancer risk reduction.[
The cost of germline genetic testing continues to decrease with advancements in DNA mutational analyses, including simultaneous testing of multiple germline variants associated with malignancy, through multigene (panel) tests. As a result, additional cost-effective analyses using more updated data related to germline testing will need to be conducted. Multigene (panel) testing may become a more favorable and cost-effective approach in the future.
Considerations and limitations related to universal tumor testing for Lynch syndrome
While universal screening continues to be adopted nationally, there is significant variability in the uptake and approach to molecular testing. A 2011 survey of the National Society of Genetic Counselors revealed that more than 25% of respondents had some form of universal screening implemented at their center. Tumor screening methods varied; 34 (64.2%) of 53 centers started with IHC, 11 (20.8%) of 53 centers started with MSI testing, and 8 (15.1%) of 53 centers performed both tests on newly diagnosed colorectal tumors.[
Because adherence to universal screening for Lynch syndrome may be poor (many patients are not referred for genetic evaluation and testing), a prospective quality improvement study utilizing the Six Sigma conceptual framework was conducted to improve the implementation of universal genetic screening among young patients with CRC.[
Studies reporting uptake of genetic testing for Lynch syndrome have largely focused on individuals and families who were selected for potential risk of Lynch syndrome based on family history or clinical characteristics. While universal tumor screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, few studies have examined the uptake of genetic testing after universal tumor testing. An important implication of universal screening for Lynch syndrome is that it does not result in automatic germline testing in appropriate individuals. In the clinical setting, more follow-up by health care teams to facilitate referral to genetic counseling for patients with abnormal tumor screening results may improve completion of genetic testing.[
Subsequent genetic counseling requires coordination between the pathologist, the referring surgeon or oncologist, and a cancer genetics service. As an illustration, a population-based screening study found that only 54% of patients with an IHC-deficient tumor (that was BRAF pathogenic variant–negative) ultimately consented to and proceeded with germline MMR testing.[
In contrast to tumor testing, which is commonly performed without a patient's prior knowledge, germline genetic testing, such as germline testing for MMR pathogenic variants, generally includes genetic counseling and requires patient permission before it is performed. A cross-sectional survey of U.S. cancer programs (20 NCI–designated Comprehensive Cancer Centers and 49 community hospital cancer programs) found that, of those that performed MSI and/or IHC testing as part of standard pathologic evaluation at the time of colon cancer diagnosis in all or select cases, none required written informed consent before tumor testing.[
Diagnostic strategies for all individuals diagnosed with endometrial cancer
Given the increased prevalence of endometrial cancer among carriers of MMR pathogenic variants, there is a growing consensus to screen patients with endometrial cancer for Lynch syndrome.
In a study that examined the feasibility and desirability of performing tumor screening of all endometrial cancers, regardless of age at diagnosis or family history of cancer, at least 2.3% (95% CI, 1.3%–4.0%) of newly diagnosed patients had Lynch syndrome.[
Another smaller study of 242 consecutive endometrial cases demonstrated a 4.5% (11/242) prevalence of MMR-deficient cases lacking somatic MLH1 promoter hypermethylation, including four cases (1.7%) with germline MMR mutations, four cases (1.7%) with two somatic MMR alterations on NGS, and two cases (0.8%) with otherwise unexplained MMR-deficiency.[
Another study prospectively evaluated universal IHC-based screening of both CRC and endometrial cancer cases, irrespective of age at diagnosis.[
The cost-effectiveness of tumor testing of women diagnosed with endometrial cancer was examined in a model-based simulation study and included IHC testing in the following scenarios: (1) diagnosis before age 50 years; (2) diagnosis before age 60 years; (3) any age at diagnosis with the presence of an FDR with any Lynch syndrome–associated cancer; and (4) all cases irrespective of diagnosis age and family history. Women fulfilling Amsterdam II criteria or those diagnosed before age 50 years with at least one FDR with any Lynch syndrome–associated cancer were directly referred for genetic counseling and genetic testing without IHC testing. A strategy of IHC testing for MMR protein expression in all patients with endometrial cancer and an FDR with any Lynch syndrome–associated cancer was reported to be cost-effective in the detection of Lynch syndrome.[
(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about endometrial cancer as a component of Lynch syndrome.)
MSI in all cancers
Use of MSI testing across all tumor types has become an important screening tool to select cases that may have a favorable response to immune checkpoint inhibitor therapy. These results may potentially be used to screen for Lynch syndrome in tumors other than CRC. A study evaluated MSI across a wide variety of malignancies and evaluated its use as a potential means to identify Lynch syndrome, regardless of tumor type.[
Germline genetic testing
Genetic testing for germline pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM can help formulate appropriate intervention strategies for the affected variant-positive individual and at-risk family members, many of whom may be unaffected by cancer.
If a pathogenic variant is identified in an affected person, then testing for that same pathogenic variant should be offered to all at-risk family members. At-risk relatives who test negative for the identified pathogenic variant in the family are not at increased risk of CRC or other Lynch syndrome–associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial pathogenic variant are referred to surveillance and management guidelines for Lynch syndrome. (Refer to the Management of Lynch syndrome section of this summary for more information.)
If no pathogenic variant is identified in the affected family member, then testing is considered negative for Lynch syndrome in that individual. With advances made in DNA sequencing technologies, it is unlikely that current gene testing is not sensitive enough to detect a pathogenic variant in the genes tested. Advances in testing, including the common use of NGS by most commercial testing laboratories have improved upon the detection of certain alterations such as large deletions or genomic rearrangements as well as the presence of a pseudogene PMSCL in PMS2.
Possible reasons why a pathogenic variant may not be detected include the following:
Failure to detect a pathogenic variant could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis (e.g., the patient may have double somatic mutations in an MMR gene). If no variant can be identified in an affected family member, testing should not be offered to at-risk members because results would be uninformative for the relatives. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening.
(Refer to the Management of Lynch syndrome section of this summary for more information.)
Multigene (panel) testing
Germline mutation analysis of MLH1, MSH2 (including EPCAM), MSH6, and PMS2 may be considered in instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC. This approach has become less expensive with the advent of multigene (panel) testing, which is now offered by several clinical laboratories at a cost that may be comparable to single-gene testing. The cost of multigene testing may also approach the cost of tumor screening and may prove to be a cost-effective approach in individuals affected by CRC. At present, multigene tests are not routinely recommended for universal screening for Lynch syndrome among all newly diagnosed CRC patients, but they may be very useful in select populations, such as those with early-onset CRC [
Individuals with early-onset CRC have been shown to have a high frequency and wide spectrum of germline pathogenic variants, indicating that panel testing in this population may be beneficial. In a study of 450 patients with early-onset CRC (mean age at diagnosis, 42.5 y) and a family history including at least one FDR with colon, endometrial, breast, ovarian, and/or pancreatic cancer, 75 germline pathogenic or likely pathogenic variants were identified in 72 patients (16%).[
Multigene testing has also been examined in a larger study of 1,058 individuals with CRC who were unselected for age at diagnosis, personal or family history, or MSI/MMR test results.[
A 2017 study examined the frequency of pathogenic Lynch syndrome–associated gene variants in individuals undergoing multigene testing at a single commercial United States laboratory between 2012 and 2015, and reported on the characteristics of those carriers identified with Lynch syndrome.[
The study reports on genotype-phenotype correlations on 528 Lynch syndrome carriers, the majority of whom had CRC (186, 35.2%) and endometrial cancer (136, 25.8%), followed by breast cancer (124, 23.5%) and ovarian cancer (74, 14%).[
Clinical criteria for the identification of Lynch syndrome, including the Amsterdam criteria, revised Bethesda guidelines, or the PREMM(1,2,6) risk prediction model, would have failed to identify 27.3% of Lynch syndrome carriers in this study.[
Lastly, germline MMR genes have been detected unexpectedly among individuals undergoing multigene testing for cancers not commonly associated with Lynch syndrome, such as breast and prostate cancer. As a result, the cancer spectrum associated with Lynch syndrome may be wider than previously appreciated. (Refer to the Breast cancer and Prostate cancer sections of this summary and the Genetics of Prostate Cancer summary for more information.)
(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.)
Cost-effectiveness of multigene (panel) testing
As genetic testing becomes routine rather than the exception, questions regarding the cost of testing are inevitable. Historically, a cost-effectiveness ratio of $50,000 per quality-adjusted life-year (QALY) has been utilized as the benchmark for good value for care.[
A 2015 study evaluated the cost-effectiveness of multigene testing for CRC and polyposis syndromes in patients referred to a cancer genetics clinic.[
The cost of germline genetic testing continues to decrease with advancements in technology since the time this model analysis was conducted; additional studies are needed to continue to assess the cost-effectiveness of this testing approach.
Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome
Lynch syndrome is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors, notably endometrial cancer. Lynch syndrome is caused by pathogenic variants in the DNA MMR genes, namely MLH1 (mutL homolog 1) on chromosome 3p21;[
Lynch syndrome accounts for about 3% of all newly diagnosed cases of CRC.[
Original reports related to overall and gene-specific prevalence estimates in Lynch syndrome relied heavily on retrospective data from familial cancer registries worldwide. Earlier risk estimates of CRC (and endometrial cancer) reported in Lynch syndrome were subject to ascertainment bias and overestimation, given that data were derived largely from familial cancer registries and cases were often ascertained based on young-onset CRC or an increased number of CRC cases among relatives. Correction of these cancer risk estimates has been made possible through modified segregation analyses, where statistical methodology provides more accurate estimates and adjusts for ascertainment bias. Conversely, risk estimates related to extracolonic malignancies, with the exception of endometrial cancer, may be prone to underestimation because many families may have underreported these cancers in relatives, and Lynch syndrome–related tumors may have occurred later in life.
In a large population-based study of 5,744 CRC cases who were recruited irrespective of family cancer history from the United States, Australia, and Canada, it was estimated that 1 in 279 individuals in the population carry an MMR pathogenic variant associated with Lynch syndrome.[
In another population-based study of 450 individuals with CRC but limited to young onset with diagnoses occurring before age 50 years, germline pathogenic variants were identified in 72 of 450 individuals (16%), as detected by multigene (panel) testing for inherited cancer susceptibility genes. As expected, the majority of identified variants were in genes known to be associated with CRC, predominantly Lynch syndrome (37 of 72 patients, 51.4%). However, 13 of 72 patients (18.1%) had pathogenic variants in genes not traditionally associated with CRC, including but not limited to BRCA1/BRCA2, which accounted for 8% of the identified variants. Because of the high frequency and wide variety of pathogenic variants identified, the authors suggested consideration of multigene testing for all individuals with early-onset CRC.[
Gene-specific considerations and associated CRC risk
The MLH1 and MSH2 genes were originally thought to account for most pathogenic variants of the MMR genes found in Lynch syndrome. However, the prevalence of MSH6 and PMS2 pathogenic variants has been increasing with improved DNA mutational analyses and universal tumor screening of all CRCs.[
In early studies, the prevalence of MLH1 pathogenic variants in individuals with Lynch syndrome was reported to be between 41.7% [
MLH1 pathogenic variants are associated with the entire spectrum of malignancies associated with Lynch syndrome.[
Unlike the APC gene of FAP, in which several phenotypes of differing severity and spectrum of disease occur, genotype-phenotype relationships have been elusive in the MMR genes. In a large series of MLH1 pathogenic variant carriers, women with truncating MLH1 pathogenic variants had significantly later onset of endometrial cancer than did those with nontruncating variants.[
The prevalence of MSH2 pathogenic variants in individuals or families with Lynch syndrome has varied across studies. MSH2 pathogenic variants were reported in 38% to 54% of Lynch syndrome families in studies including large cancer registries and among cohorts of early-onset CRC (younger than age 55 y).[
The risk of any Lynch syndrome–associated cancer by age 70 years has been found to range between 57% to nearly 80% in MSH2 pathogenic variant carriers.[
The mean age at diagnosis of CRC in MSH2 carriers has been comparable to MLH1 carriers. One study that included 143 affected individuals with MSH2 pathogenic variants found a mean age at CRC diagnosis of 43.9 years (range, 16–90 y). The same study reported a mean age at CRC diagnosis of 42.8 years (range, 16–81 y) in 137 MLH1 pathogenic variant carriers.[
Most series have reported a prevalence of germline MSH6 pathogenic variants in approximately 10% of Lynch syndrome families from high-risk clinics and a higher proportion of unselected CRC patients, at approximately 50%.[
The lifetime risk of any Lynch syndrome–associated cancer among MSH6 pathogenic variant carriers is approximately 25% [
The largest series of carriers of MSH6 pathogenic variants reported to date includes 113 families from five countries who were ascertained through family cancer clinics and population-based cancer registries.[
In a more recent prospective study using pooled European registry data of 305 MSH6 carriers without cancer, the cumulative CRC incidence was 20% at age 70 years despite colonoscopic surveillance.[
PMS2 was the last of the genes in the MMR family of genes to be identified. This was because lower penetrance among families made it more difficult to identify [
In earlier studies of individuals with CRC and suspected Lynch syndrome, the prevalence of PMS2 pathogenic variants was variable from 2.2% to 5%,[
The lifetime risk of any cancer has been found to range between 25% and 32% for heterozygous PMS2 pathogenic variant carriers.[
The PLSD is a major ongoing initiative to assess cancer risks in Lynch syndrome. Although it lacks specific details regarding screening practices, it includes outcome data from many European programs, classified by age, gender, and MMR gene.[
It is important to note that a more severe phenotype is seen among carriers of biallelic PMS2 pathogenic variants. (Refer to the BMMRD section in the Genetics of Lynch syndrome section of this summary for more information.)
The lifetime risk of CRC and endometrial cancer in carriers of these pathogenic variants is summarized in Table 11.
|Gene||Lifetime Risk of Colorectal Cancer (%)||Lifetime Risk of Endometrial Cancer (%)||References|
A subset of individuals with Lynch syndrome (approximately 1%) have a pathogenic variant in EPCAM, which leads to hypermethylation and inactivation of the MSH2 promoter.[
One study of two families with the same EPCAM deletion limited to the 3' end of the gene and not extending into the promoter of MSH2 found few extracolonic cancers and no endometrial cancers.[
As described above, patients may carry MMR gene variants in both parental alleles, in a condition known as BMMRD. (Refer to the BMMRD section in the Genetics of Lynch syndrome section of this summary for more information.)
The occurrence of such biallelic variants is associated with a characteristic but not diagnostic clinical phenotype. Clinical features include hematologic malignancies and brain tumors in children. When GI tumors occur, the age of onset is strikingly low, sometimes before age 20 years. Café au lait spots and features otherwise suggesting neurofibromatosis are characteristic. Occasionally, patients present with multiple adenomas.
Ethnic variation and founder pathogenic variants in Lynch syndrome
The frequency of MMR variants does not differ markedly from population to population, with similar frequencies identified in a host of different countries. As with hereditary breast and ovarian cancer (HBOC), there are certain variants that occur at higher frequencies within a particular ethnic group. Notable in HBOC are the commonly recurring Ashkenazi Jewish variants, so common that direct-to-consumer testing is offered for these common variants. (Refer to the Population estimates of the likelihood of having a BRCA1 or BRCA2 pathogenic variant section in the PDQ summary on the Genetics of Breast and Gynecologic Cancers and the Direct-to-Consumer [DTC] Genetic Tests section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) The ancientness of apparent founder variants is generally established by haplotype analysis. In some instances, what may appear to be a founder variant is simply a frequently recurring de novo variant.[
Among the first population findings regarding the MMR genes of Lynch syndrome was the recognition of two very common MLH1 variants in Finland, accounting for a majority of cases of Lynch syndrome in this country.[
In the United States, a deletion in exons 1–6 of the MSH2 gene has been estimated to account for as much as 20% of variants in that gene. This so-called American Founder Mutation has been determined by haplotype analysis to date back about 500 years.[
A South American study combining data from Uruguay, Colombia, Brazil, Argentina, and Chile also selected cases of interest according to Amsterdam and Bethesda features, yielding a 60% frequency of MLH1 and 40% frequency of MSH2. MSH6 and PMS2 were not evaluated. Selection bias likely influenced the frequency of variants and perhaps the relative contributions by MLH1 and MSH2. A possible founder variant in Colombia was noted.[
Although testing for commonly recurring founder variants in a given ethnic/geographic area has been considered to be a cost-effective first step when a stepwise strategy is employed, it is likely not necessary when the increasingly commonly approach of broad panel testing is undertaken as a basic strategy.
One consideration related to ethnicity is that of increased rates of consanguinity within certain populations and the subsequent risk of BMMRD. (Refer to the Biallelic mismatch repair deficiency [BMMRD] section of this summary for more information.)
Ethnic variation in the United States
In this section, the data exploring the distribution of MMR gene variants amongst differing ethnic groups in the United States are presented. The interpretation of these studies is challenging given the presence of selection and ascertainment bias. In addition, even population-based studies are limited by small sample sizes for many ethnic groups and self-reporting of ethnicity/race.
There are few data suggesting the presence of much variation in Lynch syndrome frequency according to geography or ethnicity. Within a small and/or homogeneous ethnic group the presence of founder variants may seem to increase the prevalence of variants in that particular gene. Slight differences in the proportion of MLH1 and MSH2 variants exist from one population to another. MSH6 and PMS2 have been insufficiently studied at the population level as to enable inferences about their relative frequencies.
The most representative population-based studies in the United States, such as that in Columbus, Ohio, have been overrepresented by White individuals, in accordance with their greater overall numbers. Consequently, data on minorities such as Hispanic and African American individuals suffer from smaller and less rigorously representative samples.
A study conducted in Puerto Rico considered variants in 89 Caribbean Hispanic patients with Lynch syndrome suspected on the grounds of Amsterdam criteria or Bethesda guidelines.[
Clinic-based series from California, Texas, and Puerto Rico yielded an overall variant prevalence similar to those described, with somewhat more MLH1 than MSH2, but also including MSH6 and PMS2. Presence of potential founder variants traceable back to Spain and Europe were noted.[
The closest population-based information on Lynch syndrome in Hispanic individuals is a Southern California study based on the California Tumor Registry, in which 265 patients were identified.[
The problem of small numbers is highlighted by the findings from the more truly population-based studies that have been done in the United States. In a study from Columbus, Ohio, only 8% of the consecutive series patients were African American and the proportion of Hispanic individuals as a subset of White individuals was not stated.[
Lynch syndrome in African Americans
The issues in evaluating prevalence of Lynch syndrome and cancer risks associated with MMR variants in African American individuals are similar to those in Hispanic individuals: a heterogeneous population that has been understudied. A study of clinic-based data from 13 referral centers in the United States identified 51 families with Lynch syndrome with frequencies of MMR gene variants as follows: 61% MLH1, 21% MSH2, 6% MSH6, and 12% PMS2. Age of cancer onset distribution curves were very similar to those seen in White populations.[
Risk of metachronous CRC
A hallmark feature of Lynch syndrome is that carriers of pathogenic MMR gene variants have an increased risk of development of synchronous and metachronous colorectal neoplasms. In one study of 382 individuals with Lynch syndrome from the Colon Cancer Family Registry, the incidence of metachronous CRCs was 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy.[
Risk of extracolonic malignancies associated with Lynch syndrome
Patients with Lynch syndrome are at an increased risk of other cancers, especially those of the endometrium. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population.[
The most common extracolonic malignancy in Lynch syndrome is endometrial adenocarcinoma, which affects at least one female member in about 50% of Lynch syndrome families. In addition, 50% of women with an MMR gene pathogenic variant will present with endometrial cancer as her first malignancy.[
The lifetime risk of endometrial cancer has been estimated to be from 44% in carriers of MLH1 pathogenic variants to 71% in carriers of MSH2 pathogenic variants, although some earlier studies may have overestimated risk due to ascertainment bias.[
A study of 127 women with Lynch syndrome who had endometrial cancer as their index cancer were found to be at significantly increased risk of other cancers. The following elevated risks were reported: CRC, 48% (95% CI, 27.2%–58.3%); kidney, renal pelvis, and ureter cancer, 28% (95% CI, 11.9%–48.6%); urinary bladder cancer, 24.3% (95% CI, 8.56%–42.9%; and breast cancer, 2.51% (95% CI, 1.17%–4.14%).[
In a study of 113 families that carried MSH6 pathogenic variants from the Colon Cancer Family Registry, female MSH6 carriers had a 26-fold increased incidence of endometrial cancer (HR, 25.5; 95% CI, 16.8–38.7) compared with the general population. A sixfold increased incidence of other cancers associated with Lynch syndrome (HR, 6.0; 95% CI, 3.4–10.7) was observed compared with the general population, but not among male MSH6 carriers.[
Lynch syndrome–associated endometrial cancer is not limited to the endometrioid subtype, and the spectrum of uterine tumors in Lynch syndrome may include clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed Müllerian tumors.[
Cancer risk in Lynch syndrome beyond CRC and endometrial cancer
Multiple studies demonstrate an increased risk of additional malignancies associated with Lynch syndrome, including cancers of the stomach, pancreas, ovary, small intestine, and brain, transitional cell carcinoma of the bladder, ureters, and renal pelvis, and sebaceous adenomas of the skin.[
The largest prospective study to date is of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry.[
A well-described variant of Lynch syndrome whose phenotype includes multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas) and CRC is Muir-Torre syndrome.[
|Cancer Siteb||General Population Risk (%)c||Risk in Individuals With Lynch Syndrome (%)d||References|
|CNS = central nervous system.|
| a Adapted from Syngal et al.[
|b Evolving data suggest a potential association between Lynch syndrome and breast and prostate cancers. (Refer to the Additional cancers potentially associated with Lynch syndromesection of this summary for more information about these cancers.)|
| c Howlader et al.[
|d Range of cancer risk estimates vary based on study sample size, subject ascertainment, and statistical methods.|
Additional cancers potentially associated with Lynch syndrome
Additional tumors are being considered as part of the spectrum of Lynch syndrome, but this is controversial. Breast and prostate cancers have been raised as possible Lynch syndrome–associated tumors such that MMR genes are now included on multigene (panel) tests for these cancers.
The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[
A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[
Prostate cancer was found to be associated with Lynch syndrome in a study of 198 families from two U.S. Lynch syndrome registries in which prostate cancer had not originally been part of the family selection criteria. Prostate cancer risk in relatives of carriers of MMR gene pathogenic variants was 6.3% at age 60 years and 30% at age 80 years, versus a population risk of 2.6% at age 60 years and 18% at age 80 years, with an overall HR of 1.99 (95% CI, 1.31–3.03).[
In a series of 114 ACC cases, of which 94 patients had a detailed family history assessment and Li-Fraumeni syndrome was excluded, three patients had family histories that were suggestive of Lynch syndrome. The prevalence of MMR gene pathogenic variants in 94 families was 3.2%, similar to the proportion of Lynch syndrome among unselected colorectal and endometrial cancer patients. In a retrospective review of 135 MMR gene pathogenic variant–positive Lynch syndrome families from the same program, two probands were found to have had a history of ACC. Of the four ACCs in which MSI testing could be performed, all were MSS. These data suggest that if Lynch syndrome is otherwise suspected in an ACC index case, an initial evaluation of the ACC using MSI or IHC testing may be misleading.[
Several additional cancers have been found to be associated with Lynch syndrome in some studies, but further investigation is warranted. Table 12 compares the risk of these cancers in the general population with that of individuals with Lynch syndrome.
Management of Lynch syndrome
Screening and surveillance in Lynch syndrome
Colon cancer screening and surveillance in Lynch syndrome
Several aspects of the biologic behavior of CRC and its precursor lesion, the adenomatous polyp, in individuals with Lynch syndrome support a different approach to CRC screening in this population as compared with those recommendations for average-risk people in the general population. At present, the recommendations for cancer screening and surveillance in Lynch syndrome take into account the differences in cancer risks as compared with those in the general population due to the causative germline deficiency in the MMR system. The following biological differences form the basis of the currently implemented screening strategies in Lynch syndrome:
CRCs in Lynch syndrome occur earlier in life than do sporadic cancers; however, the age of onset varies based on which of the MMR genes is altered. (Refer to the Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome section of this summary for more information about gene-specific age of onset of CRC.)
Carriers of Lynch syndrome pathogenic variants have an increased risk of developing colon adenomas and the onset of adenomas appears to occur at a younger age than in pathogenic variant–negative individuals from the same families.[
In one study, the mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23–63.2 y), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2–57.6 y).[
A larger proportion of Lynch syndrome CRCs (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Evidence-based reviews of surveillance colonoscopy in Lynch syndrome have been reported.[
The progression from normal mucosa to adenoma to cancer is accelerated,[
Evidence for the use of colonoscopy for CRC screening and surveillance in Lynch syndrome
The risk of CRC in Lynch syndrome has been studied and updated in a Finnish screening trial, which spans from the early 1980s to present.[
A 15-year controlled screening trial conducted in this series demonstrated a reduction in the incidence of CRC, CRC-specific mortality, and overall mortality with colonoscopy in individuals from Lynch syndrome families.[
The series subsequently limited its attention to subjects without prior diagnosis of adenoma or cancer. The eligible 420 carriers of pathogenic variants had a mean age of 36 years and underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about one-half were located proximal to the splenic flexure. While the rates for CRC despite colonoscopy surveillance appear high, the recommended short intervals were not regularly adhered to in this nonrandomized series. These authors recommended surveillance at 2-year intervals. This is in line with most consensus guidelines (refer to Table 13), in which the appropriate colonoscopy screening interval remains every 1 to 2 years. Analysis of colonoscopic surveillance data in 242 carriers of pathogenic variants 10 years after testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with variant-negative relatives. However, this may be attributable to the modest sample size of the study.[
Individuals with Lynch syndrome are at an increased risk of developing synchronous CRC. Of 5,304 CRC cases in the Danish HNPCC Register, including 774 with Lynch syndrome, the relative risks of synchronous CRC (>1 CRC) diagnosed within 1 year of primary CRC for Lynch syndrome, familial CRC (cases meeting Amsterdam I or II criteria) and metachronous CRC (1 CRC at age <50 y or >2 CRCs at age >50 y) were 5.6, 3.2, and 1.9, respectively, compared with sporadic CRC. Thus, the increased risk of synchronous CRC in patients with a strong family history of CRC, and especially Lynch syndrome, should be considered in preoperative colonoscopic examinations.[
Given that colonoscopy is the accepted measure for colon cancer surveillance, preliminary data suggest that the use of chromoendoscopy, such as with indigo carmine, may increase the detection of diminutive, histologically advanced adenomas.[
When an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR pathogenic variants found eight of 12 adenomas to have both MSI and IHC protein loss.[
Level of evidence (colon surveillance): 2ai
Special considerations: The impact of gene-specific variability in cancer risk on CRC screening recommendations in Lynch syndrome
Because of the variability of gene-specific CRC risks, experts in the field have proposed gene-specific screening and surveillance recommendations. For example, a European consortium [
Available recommendations for colon surveillance in individuals with Lynch syndrome are summarized in Table 13. Most organizations have adopted a gene-specific approach to these recommendations.[
|CRC = colorectal cancer; EHTG = European Hereditary Tumor Group; ESCP = European Society of Coloproctology; ESMO = European Society for Medical Oncology; MMR = mismatch repair; NCCN = National Comprehensive Cancer Network.|
| a This table summarizes available guidelines from 2014 and later. Other organizations, including the American Cancer Society, have published guidelines before 2014.[
|b U.S. Multi-Society Task Force on Colorectal Cancer includes the following organizations: American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.|
| c Consider later age forMSH6carriers.[
| d Consider repeating colonoscopy every 5 years forPMS2carriers.[
| e Consider starting at age 30 forMSH6carriers and 35 forPMS2carriers. Consider annual colonoscopy for MMR carriers.[
||Colonoscopy at age 20–25 y or 2–5 y prior to earliest CRC if diagnosed before age 25 y; repeat every 1–2 y||Colonoscopy at age 20–25 y or 2–5 y prior to earliest CRC if diagnosed before age 25 y; repeat every 1–2 y||Colonoscopy at age 30–35 y or 2–5 y prior to earliest CRC if diagnosed before age 30 y; repeat every 1–2 y||Colonoscopy at age 30–35 y or 2–5 y prior to earliest CRC if diagnosed before age 30 y; repeat every 1–2 y||EPCAM carriers should be managed as those withMSH2pathogenic variants|
||Colonoscopy at age 25 y or 5 y prior to earliest CRC if diagnosed before age 25 y; repeat every 1–2 y||Colonoscopy at age 25 y or 5 y prior to earliest CRC if diagnosed before age 25 y; repeat every 1–2 y||Colonoscopy at age 35 y or 5 y prior to earliest CRC if diagnosed before age 25 yc; repeat every 1–2 y||Colonoscopy at age 35 y or 5 y prior to earliest CRC if diagnosed before age 25 y; repeat every 1–2 y||Not addressed|
|British Society of Gastroenterology (BSG)/ Association of Coloproctology of Great Britain and Ireland (ACPGBI)/ United Kingdom Cancer Genetics Group (UKCGG) (2020)[
||Colonoscopy at age 25 y; repeat every 2 y until age 75 y||Colonoscopy at age 25 y; repeat every 2 y until age 75 y||Colonoscopy at age 35 y; repeat every 2 y until age 75 y||Colonoscopy at age 35 y; repeat every 2 y until age 75 y||EPCAMcarriers should be managed as those withMSH2pathogenic variants|
|European guidelines from the EHTG and ESCP; updated Mallorca group guidelines (2020)[
||Colonoscopy at age 25 y; repeat every 2–3 y||Colonoscopy at age 25 y; repeat every 2–3 y||Colonoscopy at age 35 y; repeat every 2–3 y||Colonoscopy at age 35 y; repeat every 2–3 yd||Not addressed|
|U.S. Multi-Society Task Force on Colorectal Cancer (2014)b[
||Colonoscopy beginning at age 20–25 y for 2–5 y prior to earliest CRC if before age 25 y; repeat every 1–2 ye|
Extracolonic cancer screening in Lynch syndrome
Gynecologic cancer screening in Lynch syndrome
Endometrial cancer screening in Lynch syndrome
Note: A separate PDQ summary on Endometrial Cancer Screening in the general population is also available.
Cancer of the endometrium is the most common extracolonic cancer observed in Lynch syndrome families, affecting at least one female in about 50% of Lynch syndrome families. (Refer to the Endometrial cancer section of this summary for more information about gene-specific risks of endometrial cancer in carriers of MMR pathogenic variants.)
In the general population, the diagnosis of endometrial cancer is generally made when women present with symptoms including abnormal or postmenopausal bleeding. Endometrial sampling is performed to provide a histologic specimen for diagnosis. Eighty percent of women with endometrial cancer present with stage I disease and there are no data to suggest that the clinical presentation in women with Lynch syndrome differs from that in the general population.
Given their substantial increased risk of endometrial cancer, endometrial screening for women with Lynch syndrome has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. TVUS continues to be widely recommended without data to support its use; current NCCN guidelines suggest that there is no clear evidence to support endometrial cancer screening for Lynch syndrome.[
A study of 175 women with Lynch syndrome, which included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity compared with TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS.[
Some studies suggest that women with a clinical or genetic diagnosis of Lynch syndrome do not universally adopt intensive gynecologic screening.[
Level of evidence: 5
Ovarian cancer screening in Lynch syndrome
Estimates of the cumulative lifetime risk of ovarian cancer in Lynch syndrome patients range from 3.4% to 22%.[
Level of evidence: None assigned
Risk-reducing surgeries for the prevention of gynecologic cancers in Lynch syndrome
An effective strategy for the prevention of endometrial and ovarian cancers in Lynch syndrome families is risk-reducing surgery. A retrospective study of 315 women with pathogenic MMR gene variants compared the rate of endometrial and ovarian cancer among the women who did and did not have hysterectomy and oophorectomy. In women followed for endometrial cancer, the mean follow-up periods were 13.3 years in the surgical group and 7.4 years in the nonsurgical group; in women followed for ovarian cancer, the mean follow-up periods were 11.2 years in the surgical group and 10.6 years in the nonsurgical groups. For those women in the surgical group, no cancers were diagnosed, compared with a 33% rate of endometrial cancer and a 5.5% rate of ovarian cancer in the nonsurgical group.[
Level of evidence: 3aii
Additional extracolonic cancer screening in Lynch syndrome
The decision to screen for other Lynch syndrome–associated cancers is done on an individual basis and relies on the cancers reported among FDRs and second-degree relatives with Lynch syndrome.
The lifetime risk of gastric cancer is approximately 8% for male Lynch syndrome carriers and 5% for female Lynch syndrome carriers.[
Level of evidence: 5
Small bowel cancer
There are variable reports on the lifetime risk of small bowel cancer associated with Lynch syndrome, ranging from less than 1% to 12%.[
Level of evidence: 5
Urinary tract cancer
Urinary tract malignancies include those of the transitional cell type of the renal pelvis and ureters, and the bladder. The associated lifetime risk of these malignancies is variable, ranging from less than 1% to as high as 25%, with higher estimates related to pooling the cancers found in different locations within the urinary tract and including the bladder.[
Level of evidence: 5
An elevated risk of pancreatic cancer among Lynch syndrome carriers has been supported by two cohort studies that adjust for ascertainment bias. One study reported a cumulative risk of pancreatic cancer of 3.7% by age 70 years and an 8.6-fold increase compared with the general population. [
Of note, screening for cancers of the urinary tract, bladder, hepatobiliary system, and pancreas is not recommended beyond that for the general population; however, NCCN suggests the consideration of urothelial cancer surveillance for individuals with a family history of urothelial cancer.[
Level of evidence: 5
Chemoprevention in Lynch syndrome
The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with Lynch syndrome who were in surveillance programs at a number of international centers.[
In 2020, long-term follow-up data with all participants having surpassed 10 years of follow-up demonstrated a significant reduction in CRC incidence for participants randomly assigned to receive aspirin both by per-protocol analysis (HR, 0.56; 95% CI, 0.34–0.91) and intention-to-treat analysis (HR, 0.65; 95% CI, 0.43–0.97).[
To date, there has been no significant preventive benefit identified in CAPP2 participants randomly assigned to receive resistant starch versus starch-placebo (HR for incident CRC, 1.40; 95% CI, 0.78–2.56, P = .26).[
Experts have speculated that certain Lynch syndrome carriers with lower risks of future incident CRCs (e.g., those with germline PMS2 pathogenic variants, those with prior colectomy, or older individuals) may be less likely to derive benefit from aspirin chemoprevention and may be appropriate for lower dosing.[
The CAPP3 trial, which is evaluating the effect of lower doses of aspirin (blinded 100 mg, 300 mg, and 600 mg enteric-coated aspirin) completed accrual of 1,882 Lynch syndrome carriers in 2019 and data are not expected until at least 5 years of follow-up is complete.[
Because of the level 1 evidence in support of aspirin chemoprevention, clinical practice guidelines consistently recommend consideration of aspirin in Lynch syndrome carriers, although most of these guidelines do make note of the ongoing uncertainties about optimal aspirin dosing.[
For Lynch syndrome carriers unable to take aspirin, it is unclear whether NSAIDs may have a comparable chemopreventive benefit. A 2015 survey of 1,858 participants in the Colon Cancer Family Registry suggested that aspirin and ibuprofen might both reduce incident CRC in Lynch syndrome carriers.[
Level of evidence: 1aii
Management of Lynch syndrome-associated CRC
Surgical management of CRC in Lynch syndrome
One of the hallmark features of Lynch syndrome is the presence of synchronous and metachronous CRCs. The incidence of metachronous CRCs has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy.[
Two studies have shown that patients who undergo extended procedures have fewer metachronous CRCs and additional surgical procedures related to CRC than do patients who undergo segmental resections.[
A retrospective study from the Creighton University Hereditary Cancer Center evaluated the incidence of metachronous CRC and survival in 64 Lynch syndrome pathogenic variant carriers with right-sided colon cancer undergoing either proximal colectomy or total or subtotal colectomy.[
When considering surgical options, it is important to recognize that a subtotal or total colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant after an abdominal colectomy has been reported to be 12% at 12 years post-colectomy.[
In patients with Lynch syndrome and rectal cancer, similar surgical options (extended vs. segmental resection) and considerations must be given. Extended procedures include restorative proctocolectomy and IPAA if the sphincter can be saved, or proctocolectomy with loop ileostomy if the sphincter cannot be saved. The risk of metachronous colon cancer after segmental resection for an index rectal cancer has been reported to be between 15% and 27%.[
There are no data about fertility after surgery in Lynch syndrome patients. In female FAP patients, no difference in fecundity after abdominal colectomy and IRA has been reported, whereas there is a 54% decrease in fecundity in patients who undergo restorative proctocolectomy with IPAA compared with the general population.[
In a large Danish registry study, the incidence rate for metachronous CRC was fivefold higher in Lynch syndrome patients, but not significantly higher in familial CRC and moderate familial risk CRC cases when compared with sporadic CRC, demonstrating that the risk of metachronous CRC occurred almost exclusively in Lynch syndrome cases.[
Most clinicians who treat patients with Lynch syndrome will favor an extended procedure at the time of CRC diagnosis. However, as stated above, the choice of surgery must be made on an individual basis by the surgeon and the patient.[
Level of Evidence: 4
Prognostic and therapeutic implications of MSI
As discussed in previous sections, MSI is not only a molecular feature of Lynch syndrome but is also present in 10% to 15% of sporadic cases of CRC (largely due to MLH1 hypermethylation or biallelic somatic mutations in an MMR gene). Although MSI testing was initially utilized to screen patients who might harbor pathogenic MMR gene variants, it has been increasingly recognized that MSI has important prognostic and therapeutic implications. The utility of MSI testing beyond identifying Lynch syndrome has made the case for universal MSI screening more compelling and has contributed to its widespread adoption. Several studies have suggested that stage-specific survival is better for MSI-H CRC compared with MSS cancers. Additionally, the chemotherapeutic agent fluorouracil (5-FU) appears ineffective in the adjuvant treatment of resected MSI-H CRC, in contrast to MSS CRC in which this agent is widely utilized for this purpose. Finally, immunomodulation with agents such as checkpoint inhibitors appears effective in the treatment of advanced MSI-H CRC based on early phase 1 and phase 2 studies, while these agents, at least when utilized as monotherapy, show little activity in MSS CRC.
Prognosis of MSI
Although MSI-H tumors account for 15% of all sporadic CRC, they appear to be more frequent in stage II compared with stage III CRC,[
Several studies subsequently confirmed the improved survival of stage II MSI-H CRC compared with MSS cases. A meta-analysis of 32 studies of 7,642 cases, including 1,277 with MSI-H, showed a combined HR estimate for overall survival (OS) associated with MSI of 0.65 (95% CI, 0.59–0.71; heterogeneity P = .16; I2 [a measure of the percentage of variation across studies that is due to heterogeneity rather than chance] = 20%).[
Consistent with other prior data, clinicopathologic analysis of 85 Lynch syndrome–associated CRCs and 67 sporadic dMMR CRCs demonstrated a significantly superior survival among patients with Lynch syndrome, as well as younger ages at diagnosis and higher numbers of tumor-infiltrating lymphocytes (TILs).[
Given the predilection for MSI-H tumors to involve the right side of the colon, there is a paucity of data on the outcome and prognosis of MSI-H tumors involving the rectum. One study suggested only 2% of rectal cancers are MSI-H.[
The use of adjuvant chemotherapy after surgery for CRC in Lynch syndrome
The finding of MSI in a CRC has been shown in several studies to predict the lack of benefit of adjuvant chemotherapy with 5-FU in resected stage II or stage III colon cancer.[
In 2003, however, the outcomes in a randomized controlled prospective trial of adjuvant chemotherapy in 570 colon cancer patients demonstrated no benefit from adjuvant 5-FU in the group with MSI. Moreover, there were nonsignificant trends towards increased mortality when colon cancers with MSI were treated: twofold for stage III cancers and threefold for stage II cancers.[
Preclinical data suggests the addition of oxaliplatin to 5-FU can overcome the resistance to 5-FU monotherapy seen in MSI-H tumors.[
Level of evidence (against the use of adjuvant therapy): 1ai
Tumors that develop via the MSI pathway have more somatic mutations than tumors that develop via other pathways. This could imply that dMMR tumors may have more potential antigens (termed neoantigens) and may be more responsive to immune system manipulation than proficient MMR (pMMR) tumors. Microscopically, MSI-H tumors often exhibit abundant tumor-infiltrating lymphocytes, sometimes resulting in a Crohn-like reaction. This histologic feature has long suggested the possibility of increased tumor immune surveillance in MSI-H cancers and is one of the main hypotheses for the better stage-specific survival seen in MSI-H compared with MSS cancers.
To test the hypothesis of efficacy of immunomodulation in MSI-H tumors, a phase 2 trial of programmed cell death-1 (PD-1) inhibition was carried out in a small cohort of patients with MSI-H or MSS cancers. Patients with metastatic disease that had failed various chemotherapy regimens were treated with pembrolizumab, an anti–PD-1 immune checkpoint inhibitor.[
A single-arm phase 2 study (CheckMate 142) of another PD-1 inhibitor, nivolumab, was performed in 74 patients with MSI-H/dMMR CRC that had progressed on prior cytotoxic chemotherapy (including 5-FU, irinotecan, and oxaliplatin).[
Based on these data, pembrolizumab 200 mg given intravenously every 3 weeks was approved by the FDA in May 2017 for the treatment of any MSI-H/dMMR metastatic cancer that is refractory to standard therapy and nivolumab 240 mg given intravenously every 2 weeks was granted accelerated approval by the FDA in August 2017 for the treatment of MSI-H/dMMR CRC that is refractory to cytotoxic chemotherapy.
In 2020, treatment-naïve patients with MSI-H/dMMR CRC were enrolled in a phase III trial (KEYNOTE-177) where they were randomized to receive pembrolizumab or chemotherapy. Patients who received pembrolizumab had an increase in PFS when compared with patients who received chemotherapy.[
In another arm of CheckMate 142, 119 individuals with metastatic dMMR CRC were treated with nivolumab plus ipilimumab.[
There is debate about when immunotherapeutic agents can be used in patients with non-CRC, MSI-H cancers. Many providers question in which line of therapy immunotherapeutics should be initiated. This question is the subject of multiple ongoing clinical trials. (Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria.)
Level of evidence: 3b
Vaccines in the treatment or prevention of MSI-related CRC
An alternative approach to immunotherapy in MSI-H CRC involves the use of tumor-directed vaccines. The most promising approaches thus far involve the use of tumor-related neoantigens as epitopes to increase tumor-specific T-cell immunity. Studies are currently under way in the adjuvant treatment of resected stage III CRC (NCT01461148), in patients with metastatic disease (NCT01885702), and in the prevention of CRC in patients with Lynch syndrome (NCT01885702).
Lynch syndrome–related syndromes
Lynch-like or HNPCC-like syndrome
Lynch-like syndrome may account for up to 70% of cases in which Lynch syndrome is suspected but germline testing fails to identify a pathogenic MMR gene variant.[
Possible explanations for the cause of Lynch-like syndrome include the following: (1) the possibility that some germline DNA variants are not detected by current testing; (2) affected individuals may have germline pathogenic variants in genes other than DNA MMR genes currently known to be associated with Lynch syndrome; or (3) there are other mechanisms that inactivate DNA MMR beyond those related to alterations in the germline.
There is growing evidence that the CRC risk among probands and families with Lynch-like syndrome are lower, with an SIR of 2.12, than in Lynch syndrome, with an SIR of 6.04.[
Familial colorectal cancer type X
The term familial colorectal cancer type X or FCCX was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities.[
Advances in Endoscopic Imaging in Hereditary CRC
Performance of endoscopic therapies for adenomas in FAP and Lynch syndrome, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and Lynch syndrome the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in Lynch syndrome.
The need for sensitive means to endoscopically detect subtle polyps has increased with the recognition of flat adenomas and sessile serrated polyps in otherwise average-risk subjects, very attenuated adenoma phenotypes in AFAP, and subtle flat adenomas in Lynch syndrome. Modern high-resolution endoscopes improve adenoma detection yield, but the use of various vital dyes, especially indigo carmine dye-spray, has further improved detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue),[
In various large series of average-risk populations, subtle flat lesions were detected in about 5% to 10% of cases, including adenomas with high-grade dysplasia and invasive adenocarcinoma.[
In a randomized trial of subjects with Lynch syndrome,[
In a German study,[
Fewer evaluations of chromoendoscopy have been performed in AFAP than in Lynch syndrome. One study examined four patients with presumed AFAP and fewer than 20 adenomas upon white-light examination.[
A similar role for chromoendoscopy has been suggested to evaluate the duodenum in FAP. One study from Holland that used indigo carmine dye-spray to detect duodenal adenomas showed an increase in the number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.[
Small bowel imaging
Patients with PJS and JPS are at greater risk of disease-related complications in the small bowel (e.g., bleeding, obstruction, intussusception, or cancer). FAP patients, although at great risk of duodenal neoplasia, have a relatively low risk of jejunoileal involvement. The RR of small bowel malignancy is very high in Lynch syndrome, but absolute risk is less than 10%. Although the risks of small bowel neoplasia are high enough to warrant consideration of surveillance in each disease, the technical challenges of doing so have been daunting. Because of the technical challenges and relatively low prevalences, there is virtually no evidence base for small-bowel screening in Lynch syndrome.
Historically, the relative endoscopic inaccessibility of the mid and distal small bowel required radiographic measures for its evaluation, including the barium small bowel series or a variant called tube enteroclysis, in which a nasogastroduodenal tube is placed so that all of the contrast goes into the small intestine quickly and undiluted by gastric juice for more precise imaging. None of these measures were sensitive for small lesions. Previously, therapeutic removal of lesions required laparotomy. However, multiple novel endoscopic approaches have been developed to overcome the technical limitations of small bowel endoscopy, which has enabled jejunal and ileal access for purposes of polypectomy.
For patients with PJS, double-balloon endoscopy or other forms of deep enteroscopy (single-balloon overtube or spiral overtube) are the preferred methods for evaluation of the small bowel.[
In FAP, data from capsule endoscopy [
Capsule endoscopy in the small series of PJS patients described above [
Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families,[
Familial colorectal cancer type X (FCCX)
Families meeting Amsterdam-I criteria for Lynch syndrome who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic Lynch syndrome and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCCX,[
The genetic etiology of FCCX remains unclear. Utilizing whole-genome linkage analysis and exome sequencing, a truncating variant in ribosomal protein S20 (RPS20), a ribosomal protein gene, was identified in four individuals with CRC from an FCCX family.[
Subsequent to these initial studies, several other putative FCCX genes have been found in familial, non-Lynch syndrome clusters of CRC including the polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) gene,[
Age of CRC onset in Lynch syndrome ranges from 44 years (registry series) to a mean of 52 years (population-based series).[
Rare Syndromes With Associated Colorectal Cancer Susceptibility
PTENhamartoma tumor syndromes (including Cowden syndrome)
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes (PHTS). Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable PTEN pathogenic variant.[
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. PTEN pathogenic variants are diverse and can present as nonsense, missense, frameshift, or splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif; several recurrent pathogenic variants have been observed at this location.[
Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[
Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTEN testing in the United States, Europe, and Asia.[
The age-adjusted risk of CRC was increased in carriers of pathogenic variants in both studies (SIR, 5.7–10.3).[
|Cancer||Age-Adjusted SIR (95% CI)||Age-Related Penetrance Estimates|
|CI = confidence interval; SIR = standardized incidence ratio.|
| a Adapted from Tan et al.[
| b Other historical studies have suggested a lower lifetime risk of breast cancer, in the range of 25%–50%.[
|Breast||25.4 (19.8–32.0)||85% starting around age 30 yb|
|Colorectal||10.3 (5.6–17.4)||9% starting around age 40 y|
|Endometrial||42.9 (28.1–62.8)||28% starting around age 25 y|
|Kidney||30.6 (17.8–49.4)||34% starting around age 40 y|
|Melanoma||8.5 (4.1–15.6)||6% with earliest age of onset at 3 y|
|Thyroid||51.1 (38.1–67.1)||35% at birth and throughout life|
Peutz-Jeghers syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[
Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.
|Site||Age (y)||Cumulative Risk (%)b||Reference(s)|
|GI = gastrointestinal.|
| a Reprinted with permission from Macmillan Publishers Ltd: Gastroenterology[
|b All cumulative risks were increased compared with the general population (P< .05), with the exception of cervix and testes.|
|c GI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.|
| d Westerman et al.: GI cancer does not include pancreatic cancer.[
|e Did not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.|
PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[
Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[
Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein. No strong genotype-phenotype correlations have been identified.[
STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in STK11, studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS.[
The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.
Juvenile polyposis syndrome (JPS)
JPS is a genetically heterogeneous, rare, childhood- to early adult-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract, although colorectal polyps predominate.[
JPS is caused by germline pathogenic variants in the SMAD4 gene, also known as MADH4/DPC4, at chromosome 18q21 [
Genotype/phenotype correlations suggest SMAD4 variants may be associated with a greater risk of severe gastric polyposis [
JPS patients with SMAD4 pathogenic variants may also have signs and symptoms of HHT, such as arteriovenous malformations, mucocutaneous telangiectasias, digital clubbing, osteoarthropathy, hepatic arteriovenous malformations, and cerebellar cavernous hemangioma, suggesting that the two syndromes overlap.[
Surveillance for HHT has been suggested in JPS patients with germline SMAD4 pathogenic variants.[
A severe form of JPS, in which polyposis develops in the first few years of life, is referred to as JPS of infancy. JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN. (Refer to the PTEN hamartoma tumor syndromes [including Cowden syndrome] section of this summary for more information about PTEN.) The phenotype often includes features such as macrocephaly and developmental delay, possibly as a result of loss of PTEN function.[
Juvenile polyposis gene(s)
JPS is caused by germline pathogenic variants in the SMAD4 gene in approximately 15% to 60% of cases, and to pathogenic variants in BMPR1A in approximately 25% to 40% of cases.[
SMAD4 encodes a protein that is a component of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline pathogenic variants in SMAD4 predispose individuals to forming juvenile polyps and cancer,[
BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with JPS who did not have identifiable pathogenic variants in SMAD4. Variants in BMPR1A include nonsense, frameshift, missense, and splice-site variants.[
Several studies initially suggested that a subset of families with hereditary breast and colon cancers may have a cancer family syndrome caused by a pathogenic variant in the CHEK2 gene.[
Similar results were obtained in another study conducted in Poland.[
(Refer to the CHEK2 section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
Hereditary mixed polyposis syndrome (HMPS)
HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas, atypical juvenile polyps and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[
Although exceedingly rare, GREM1 pathogenic variants have been described in several additional families of Ashkenazi Jewish ancestry, with varying clinical presentations. Although polyposis appears to be a unifying feature in most families, there is a high degree of variability with respect to polyp number, histology, and age of onset. In addition, extracolonic malignancies have been described in several pathogenic variant carriers, although the small number of affected individuals limits the ability to definitively demonstrate a causal link to the GREM1 pathogenic variant. On the basis of relatively limited data, it is reasonable to consider GREM1-variant analysis in Ashkenazi Jewish families presenting with unexplained polyposis and/or familial CRC.[
Serrated polyposis syndrome (SPS)/Hyperplastic polyposis syndrome (HPS)
Isolated and multiple hyperplastic polyps (HPs) (typically white, flat, and small) are common in the general population, and their presence does not suggest an underlying genetic disorder. Historically, the clinical diagnosis of SPS, as defined by WHO, must satisfy one of the following criteria:
Other groups have included serrated adenomas as part of the revised clinical criteria for SPS.[
Although the vast majority of cases of SPS lack a family history of HPs, approximately half of the SPS cases have a positive family history of CRC.[
The WHO criteria are based on expert opinion; there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Two studies have reported potentially causative germline variants in SPS individuals.[
In a study of 38 patients with more than 20 HPs, a large (>1 cm) HP, or HPs in the proximal colon, molecular alterations were sought in the base-excision repair genes MBD4 and MUTYH.[
In a cohort of 40 SPS patients, defined as having more than five HPs or more than three HPs, two of which were larger than 1 cm in diameter, one patient was found to have a germline variant in the EPHB2 gene (D861N).[
Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in SPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF mutation (V600E) was found in polyp tissue.[
Many of the genetic and histological alterations found in HPs of patients with SPS are common with the CIMP pathway of colorectal adenocarcinoma. Sporadic serrated polyps are the precursors to CRCs of the CIMP pathway. (Refer to the CIMP and the serrated polyposis pathway section in the Introduction section of this summary for more information.)
Interventions for rare colon cancer syndromes
Individuals with PJS and JPS are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Because of the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion).[
|Organization||STK11Gene Testing Recommendeda||Age Colon Screening Initiated||Frequency||Method||Extracolonic Screening Recommendations||Comment|
|C = colonoscopy; NCCN = National Comprehensive Cancer Network.|
|a STK11testing includes sequencing followed by analysis for deletions (e.g., multiplex ligation-dependent probe amplification), if no variant found by sequencing.|
|b Lung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.|
|(Refer to the Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancersection in the PDQ summary on the Genetics of Breast and Gynecologic Cancersfor more information about PJS and the risk of breast and ovarian cancer.)|
|Johns Hopkins (2006)[
||Yes, at age 8 y||18 y||2–3 y||C||Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes|
|Johns Hopkins (2007)[
||Yes, age not specified||Late teens or at onset of symptoms||3 y||C||Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes||Genetic testing in the late teens or at onset of symptoms|
|Cleveland Clinic (2007)[
||18 y||3 y||C||Breast, gynecologic (cervix, ovaries), pancreas, small intestine, stomach, testes|
|Erasmus University Medical Center (2010)[
||25–30 y||C||Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach|
||No specific recommendation||Late teens||2–3 y||C||Breast (women), gynecologic (cervix, ovaries, uterus), lungb, pancreas, small intestine, stomach, testes||Refer to specialized team|
Level of evidence: 5
|Organization/ Author||SMAD4 / BMPR1ATesting Recommendeda||Age Screening Initiated||Frequency||Method||Comment|
|C = colonoscopy; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; NCCN = National Comprehensive Cancer Network.|
| a SMAD4/BMPR1Atesting includes sequencing followed by analysis for deletions (e.g., multiplex ligation-dependent probe amplification), if no variant found by sequencing.[
|Cleveland Clinic (2007)[
||15 y||3 y||C, EGD||Some families withSMAD4pathogenic variant also have HHT; these individuals may need to be screened for HHT|
|Johns Hopkins (2007)[
||Yes, genetic testing preferred over C||15 y or at onset of symptoms||Yearly until polyp free then every 2–3 y||C||Prophylactic surgery if >50–100 polyps, unable to manage endoscopically, severe GI bleeding, JPS with adenomatous changes, strong family history of CRC|
|St. Mark's (2012)[
||Yes, genetic testing at age 4 y||12 y||1–3 y based on severity||C, EGD||Consider HHT workup|
||Yes||15 y||2–3 y with shorter interval if polyps are found||C||Refer to specialized team. In families without an identified pathogenic variant, consider extending colonoscopy/upper endoscopy intervals in at-risk individuals who have no polyps from 2–3 y to 5 y beginning at age 20, and then every 10 y beginning at age 40 y|
Level of evidence: 5
Psychosocial research in cancer genetic counseling and testing focuses on the interest in testing among populations at varying levels of disease risk, psychological outcomes, interpersonal and familial effects, and cultural and community reactions. This research also identifies behavioral factors that encourage or impede surveillance and other health behaviors. Data resulting from psychosocial research can guide clinician interactions with patients and may include the following:
This section of the summary will focus on psychosocial aspects of genetic counseling and testing for Lynch syndrome, familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome (PJS), including issues surrounding medical screening, risk-reducing surgery, and chemoprevention for these syndromes.
Psychosocial Issues in Lynch Syndrome
Participation in genetic counseling and testing for Lynch syndrome
Early research on genetic counseling/testing uptake
Early studies that evaluated the uptake of genetic counseling and testing focused on selected, high-risk research populations, including colorectal cancer (CRC) patients and unaffected family members identified at high risk of CRC largely based on family history. The participants were recruited mainly from clinical settings and familial colon cancer registries. Most studies recruited index cancer cases, typically CRCs, specifically to offer genetic counseling and germline testing for mismatch repair (MMR) variants; these were frequently offered as free services.[
Uptake of genetic counseling and germline testing following universal tumor screening for microsatellite instability (MSI) and/or immunohistochemistry (IHC)
While these early studies of genetic testing uptake offered preliminary insight regarding why individuals may or may not be motivated to have testing, the process for offering genetic counseling and testing differed from what has evolved into current clinical practice. Clinical practice relies less solely on family history to identify individuals who may benefit from testing, and instead utilizes universal molecular diagnostic testing of CRC and endometrial cancer tumors in newly diagnosed patients using MSI and/or IHC as an initial screen for Lynch syndrome. (Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for more information.)
While universal MSI/IHC screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, an important implication is that not all individuals who may be appropriate for germline testing follow through with recommended genetic counseling and testing services. Two reports from a single institution found that 20% and 13% of CRC and endometrial cancer index cases, respectively, with abnormal IHC results followed through with germline variant testing for Lynch syndrome.[
In a study of 145 patients with CRC in the Kaiser Permanente Northwest health care system who were surveyed before receiving their MSI results, most patients had a positive attitude toward MSI/IHC screening.[
Education regarding family history and cancer risk and encouragement to have testing from health care providers may facilitate uptake of genetic counseling and testing. A small (n = 19) qualitative study of newly diagnosed patients with CRC who met high-risk criteria for referral to cancer genetics risk assessment and counseling identified potential reasons why patients may not seek counseling as recommended. These reasons included incomplete knowledge of family cancer history and not realizing the relevance of family history to their personal cancer diagnosis; lack of a specific, direct physician's recommendation for counseling; and viewing counseling as a lower priority than coping with the immediate demands of a new cancer diagnosis.[
Uptake of cascade screening by at-risk relatives
There is increasing adoption of universal screening of newly diagnosed tumors for Lynch syndrome in clinical practice. However, the clinical benefit and cost-effectiveness of this process have been attributed to uptake of cascade screening, or predictive testing among at-risk relatives of index cancer cases who are found to have a pathogenic germline variant. A systematic review evaluated the frequency and predictors of genetic testing uptake by first-degree relatives (FDRs) of index cases with Lynch syndrome.[
A large retrospective study of genetic testing uptake across three generations of Finnish families enrolled in a Lynch syndrome registry also found an incomplete uptake of predictive testing among at-risk relatives of individuals with pathogenic variants, and a decreasing uptake rate by generation.[
Published reports of interventions to increase uptake of cascade screening in Lynch syndrome families are limited. An Australian paper compared two approaches for informing at-risk relatives about pathogenic variants for hereditary cancers, including Lynch syndrome.[
Refer to the Ethical, Legal, and Social Implications section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for information about ethical concerns, including duty to warn.
Psychological impact of participating in genetic counseling and testing for Lynch syndrome
Studies have examined the psychological status of individuals before, during, and after genetic counseling and testing for Lynch syndrome. Some studies have included only persons with no personal history of any Lynch syndrome–associated cancers,[
Several longitudinal studies have evaluated psychological outcomes before genetic counseling and testing for Lynch syndrome and at multiple time periods in the year after disclosure of test results. One study examined changes in anxiety based on personal cancer history, gender, and age (younger than 50 y vs. older than 50 y) before and 2 weeks after a pretest genetic-counseling session. Affected and unaffected female participants in both age groups and affected men older than 50 years showed significant decreases in anxiety over time. Unaffected men younger than 50 years maintained low levels of anxiety; however, affected men younger than 50 years showed no reductions in the anxiety levels reported at the time of pretest counseling.[
A limited number of studies have examined longer-term psychosocial outcomes after Lynch syndrome genetic counseling and testing.[
Findings from some studies suggested that there may be subgroups of individuals at higher risk of psychological distress after disclosure of test results, including those who present with relatively higher scores on measures of general or cancer-specific distress before undergoing testing.[
Studies also have examined the effect of Lynch syndrome genetic counseling and testing on cancer risk comprehension. One study reported that nearly all carriers and noncarriers of pathogenic variants could accurately recall the test result 1 year after disclosure. More noncarriers than carriers correctly identified their risk of developing CRC at both 1 month and 1 year after result disclosure. Carriers of pathogenic variants who incorrectly identified their CRC risk were more likely to have had lower levels of pretest subjective risk perception compared with those who correctly identified their level of risk.[
Psychosocial aspects of screening and risk reduction interventions for Lynch syndrome
Colorectal screening for Lynch syndrome
Benefits of genetic counseling and testing for Lynch syndrome include the opportunity for individuals to learn about options for the early detection and prevention of cancer, including screening and risk-reducing surgery. Studies suggest that many individuals at risk of Lynch syndrome may have had some CRC screening before genetic counseling and testing, but most are not likely to adhere to Lynch syndrome screening recommendations. Among individuals aged 18 years or older who did not have a personal history of CRC and who participated in U.S.-based research protocols offering genetic counseling and testing for Lynch syndrome, between 52% and 62% reported ever having had a colonoscopy before genetic testing.[
In a study of cancer-affected and cancer-unaffected individuals who fulfilled clinical criteria for Lynch syndrome, 92% reported having had a colonoscopy and/or flexible sigmoidoscopy at least once before genetic testing.[
Three studies determined whether cancer-unaffected individuals adhered to Lynch syndrome colonoscopy screening recommendations before genetic testing, and reported adherence rates of 10%,[
Several longitudinal studies examined the use of screening colonoscopy by cancer-unaffected individuals after undergoing testing for a known Lynch syndrome pathogenic variant.[
Two studies examined the level of adherence to published screening guidelines after Lynch syndrome genetic testing, based on variant status. One study reported a colonoscopy adherence rate of 100% among carriers of pathogenic variants.[
The longitudinal studies described above examined colorectal screening behavior within a relatively short period of time (1 year) after receiving genetic test results, and less is known about longer-term use of screening behaviors. A longitudinal study (N = 73) that examined psychological and behavioral outcomes among cancer-unaffected individuals at 3 years after disclosure of genetic test results found that all carriers (n = 19) had undergone at least one colonoscopy between 1 and 3 years postdisclosure.[
Less is known about Lynch syndrome screening behaviors in individuals who may be at risk of having a germline pathogenic variant but who do not undergo genetic counseling and/or genetic testing to learn about their risk status. Among relatives of carriers of a Lynch syndrome germline pathogenic variant from the Australian Colorectal Cancer Family Registry, 26 who had not undergone genetic counseling and/or testing completed an interview to assess their perceived risk of developing CRC in the next 10 years and to self-report their colonoscopy status.[
Gynecologic cancer screening in Lynch syndrome
Several small studies have examined the use of screening for endometrial and ovarian cancers associated with Lynch syndrome (refer to Table 18). There are several limitations to these studies, including small sample sizes, short follow-up, retrospective design, reliance on self-report as the data source, and some not including patients who had undergone Lynch syndrome genetic testing. Several studies have included individuals in the screening uptake analysis who do not meet the minimum age criteria for undergoing screening. Of the studies that assessed screening use after a negative test result for a known pathogenic variant in the family, only a few assessed indications for that screening, such as follow-up of a previously identified abnormality. Last, some studies have included patients in the uptake analysis who were actively undergoing treatment for another cancer, which could influence provider screening recommendations. Therefore, Table 18 is limited to studies with patients who had undergone Lynch syndrome genetic testing, larger sample sizes, longer follow-up, and analysis that included individuals of an appropriate screening age.
|Study Citation||Study Population||Uptake of Gynecologic Screening Before Genetic Counseling and Testing||Uptake of Gynecologic Screening After Receipt of Genetic Test Results||Length of Follow-up||Comments|
|EC = endometrial cancer; ES = endometrial sampling; RRH = risk-reducing total abdominal hysterectomy; RRSO = risk-reducing salpingo-oophorectomy; TVUS = transvaginal ultrasound.|
|Noncarrier(s) = negative for known pathogenic variant in family.|
|1 Prospective study design.|
|2 Retrospective study design.|
|a Self-report as data source.|
|Claes et al. (2005)1,a[
||Carriers (n = 7)||Not reported||TVUS||1 y||One noncarrier reported undergoing TVUS for a previous endometrial problem, while three noncarriers reported undergoing the procedure for preventive reasons|
|– Carriers 86% (6/7)|
|Noncarriers (n = 16)|
|– Noncarriers 27% (4/15)|
|Collins et al. (2007)1,a[
||Carriers (n = 13)||Not reported||TVUS||3 y||Two of four carriers had an RRH/RRSO by the 3-year follow-up assessment|
|– Carriers 69% (9/13)|
|– Noncarriers 6% (2/32)|
|Noncarriers (n = 32)||ES|
|– Carriers 54% (7/13)|
|– Noncarriers 3% (1/32)|
|Yurgelun et al. (2012): Cohort 12,a[
||77 at risk of Lynch syndrome–associated EC; 45 carriers; 19 no genetic testing but Lynch syndrome–associated family history||75% (58/77) engaged in EC screening or EC risk-reduction intervention; 42 underwent annual TVUS and/or ES; 16 underwent RRH||Not reported||N/A|
|Yurgelun et al. (2012): Cohort 21,a[
||40 women at clinical risk of Lynch syndrome||65% (26/40) adhered to EC screening or risk reduction; 6 underwent RRH; 13 underwent annual ES and/or TVUS; 6 had not reached recommended screening age||Carriers: 100% (n = 16) adhered to EC screening or risk-reducing strategies; 4 underwent pretest RRH; 5 underwent RRH; 5 underwent EC screening (TVUS and/or ES); 2 had not reached recommended screening age||1 y|
|Carriers (n = 16)|
|Noncarriers (n = 9); 14 indeterminate results; 1 variant of uncertain significance||Noncarriers: 11% (1/9) underwent EC screening; 11% (1/9) underwent RRH|
Overall, these studies have included relatively small numbers of women and suggest that screening rates for Lynch syndrome–associated gynecologic cancers are low before genetic counseling and testing. However, after participation in genetic education and counseling and the receipt of Lynch syndrome pathogenic variant test results, uptake of gynecologic cancer screening in carriers generally increases, while noncarriers decrease use.
There is no consensus regarding the use of risk-reducing colectomy for Lynch syndrome, and little is known about decision-making and psychological sequelae surrounding risk-reducing colectomy for Lynch syndrome.
Among individuals who received positive test results, a greater proportion indicated interest in having risk-reducing colectomy after disclosure of results than at baseline.[
In a cross-sectional quality-of-life and functional outcome survey of Lynch syndrome patients with more extensive (subtotal colectomy) or less extensive (segmental resection or hemicolectomy) resections, global quality-of-life outcomes were comparable, although patients with greater extent of resection described more frequent bowel movements and related dysfunction.[
Family communication about genetic testing for hereditary CRC susceptibility, and specifically about the results of such testing, is complex. It is generally accepted that communication about genetic risk information within families is largely the responsibility of family members themselves. A few studies have examined communication patterns in families who had been offered Lynch syndrome genetic counseling and testing. Studies have focused on whether individuals disclosed information about Lynch syndrome genetic testing to their family members, to whom they disclosed this information, and family-based characteristics or issues that might facilitate or inhibit such communication. These studies examined communication and disclosure processes in families after notification by health care professionals about a Lynch syndrome predisposition and have comprised relatively small samples.
Research findings indicate that individuals are generally willing to share information about the presence of a Lynch syndrome pathogenic variant within their families.[
One Finnish study recruited parents aged 40 years or older and known to carry an MMR pathogenic variant to complete a questionnaire that investigated how parents shared knowledge of genetic risk with their adult and minor offspring. The study also identified challenges in the communication process.[
In regard to informing second- and third-degree relatives, individuals may favor a cascade approach; for example, it is assumed that once a relative is given information about the family's risk of Lynch syndrome, he or she would then be responsible for informing his or her FDRs.[
While communication about genetic risk is generally viewed as an open process, some communication barriers were reported across studies. Reasons for not informing a relative included lack of a close relationship and lack of contact with the individual; in fact, emotional, rather than relational, closeness seemed to be a more important determinant of the degree of risk communication. A desire to not worry relatives with information about test results and the perception that relatives would not understand the meaning of this information also have been cited as communication barriers.[
For most participants in these studies, the news that the pattern of cancers in their families was attributable to a Lynch syndrome–predisposing pathogenic variant did not come as a surprise,[
In some cases, probands reported feeling particularly obliged to inform family members about a hereditary cancer risk [
Various modes of communication (e.g., in-person, telephone, or written contact) may typically be used to disclose genetic risk information within families.[
Much of the literature to date on family communication has focused on disclosure of test results; however, other elements of family communication are currently being explored. One study evaluated the role of older family members in providing various types of support (e.g., instrumental, emotional, crisis help, and dependability when needed) among individuals with Lynch syndrome and their family members (206 respondents from 33 families).[
Psychosocial Issues in Familial Adenomatous Polyposis (FAP)
Participation in genetic counseling and testing for FAP
The uptake for genetic testing for FAP may be higher than testing for Lynch syndrome. A study of asymptomatic individuals in the United States at risk of FAP who were enrolled in a CRC registry and were offered genetic counseling found that 82% of adults and 95% of minors underwent genetic testing.[
Genetic testing for FAP is presently offered to children with affected parents, often at the age of 10 to 12 years, when endoscopic screening is recommended. Because it is optimal to diagnose FAP before age 18 years to prevent CRC and because screening and possibly surgery are warranted at the time an individual is identified as a carrier of an APC pathogenic variant, genetic testing of minors is justified in this instance. (Refer to the Testing in children section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed discussion regarding the ethical, psychosocial, and genetic counseling issues related to genetic testing in children.)
In a survey conducted in the Netherlands of members of families with FAP, one-third (34%) believed that it was most suitable to offer APC gene testing to children before age 12 years, whereas 38% preferred to offer testing to children between the ages of 12 and 16 years, when children would be better able to understand the DNA testing process. Only 4% felt that children should not undergo DNA testing at all.[
Results of qualitative interview data from 28 U.S. parents diagnosed with FAP showed that 61% favored genetic testing of APC variants in their at-risk children (aged 10–17 y); 71% believed that their children should receive their test results. The primary reasons why parents chose to test their children included early detection and management, reduction in parental anxiety and uncertainty, and help with decision making regarding surveillance. Reasons provided for not testing focused on discrimination concerns and cost.[
Clinical observations suggest that children who have family members affected with FAP are very aware of the possibility of risk-reducing surgery, and focus on the test result as the factor that determines the need for such surgery.[
Psychological impact of participating in genetic counseling and testing for FAP
Studies evaluating psychological outcomes after genetic testing for FAP suggest that some individuals, particularly carriers of pathogenic variants, may be at risk of experiencing increased distress. In a cross-sectional study of adults who had previously undergone APC genetic testing, those who were carriers of pathogenic variants exhibited higher levels of state anxiety than noncarriers and were more likely to exhibit clinically significant anxiety levels.[
In a cross-sectional Australian study focusing on younger adults aged 18 to 35 years diagnosed with FAP (N = 88), participants most frequently reported the following FAP-related issues for which they perceived the need for moderate-to-high levels of support or assistance: anxiety regarding their children's risk of developing FAP, fear about developing cancer, and uncertainty about the impact of FAP.[
Another large cross-sectional study of FAP families conducted in the Netherlands included individuals aged 16 to 84 years who either had an FAP diagnosis, were at 50% risk of having an APC pathogenic variant, or were proven APC noncarriers.[
Another cross-sectional study conducted in the Netherlands found that among FAP patients, 37% indicated that the disease had influenced their desire to have children (i.e., wanting fewer or no children). Thirty-three percent indicated that they would consider PND for FAP; 30% would consider PGT. Higher levels of guilt and more positive attitudes towards terminating pregnancy were associated with greater interest for both PND and PGT.[
The psychological vulnerability of children undergoing testing is of particular concern in genetic testing for FAP. Research findings suggest that most children do not experience clinically significant psychological distress after APC testing. As in studies involving adults, however, subgroups may be vulnerable to increased distress and would benefit from continued psychological support. A study of children who had undergone genetic testing for FAP found that their mood and behavior remained in the normal range after genetic counseling and disclosure of test results. Aspects of the family situation, including illness in the mother or a sibling were associated with subclinical increases in depressive symptoms.[
Psychosocial aspects of screening and risk reduction interventions for FAP
Colorectal screening for FAP
Less is known about psychological aspects of screening for FAP. One study of a small number of individuals (aged 17–53 y) with a family history of FAP who were offered participation in a genetic counseling and testing protocol found that among those who were asymptomatic, all reported undergoing at least one endoscopic surveillance before participation in the study.[
When individuals at risk of FAP develop multiple polyps, risk-reducing surgery in the form of subtotal colectomy or proctocolectomy is the only effective way to reduce the risk of CRC. Most persons with FAP can avoid a permanent ostomy and preserve the anus and/or rectum, allowing some degree of bowel continence. (Refer to the Interventions for FAP section of this summary for more information about surgical management procedures in FAP.) Evidence on the quality-of-life outcomes from these interventions continues to accumulate and is summarized in Table 19.
|Population||Length of Follow-up||Type of Procedure||Stool Frequency||Stool Continence||Body Image||Sexual Functioning||Comments|
|EORTC QLQ = European Organisation for Research and Treatment of Cancer Colorectal Quality of Life Questionnaire; IPAA = ileal pouch-anal anastomosis; IRA = ileorectal anastomosis; SD = standard deviation; SF-36 = Short Form (36) Health Survey.|
|a EORTC QLQ-C38 scores range from 0–100. Functional scales: 0 = lowest level of function and 100 = highest/healthy level of function. Symptom scales: 0 = lowest level of symptomatology and 100 = highest level of symptomatology.|
|b SF-36scores range from 0–100, with 0 = lowest possible health status and 100 = best possible health status.|
|c Within normal ranges for same age group.|
|279 FAP-affected individuals (135 females and 144 males) after colectomy; controls included 1,771 individuals from the general Dutch population[
||IRA mean: 12 y (SD, 7.5 y)||IRA: n = 161||Not assessed||Not assessed||EORTC QLQ-CR38 a||EORTC QLQ-CR38 a||SF-36b scores (Dutch version) on all subscales were significantly lower than the scores in the general population (IRA:P< .001; IPAA:P< .001)|
|IRA: 87.5 (SD, 21.9)||IRA: 38.9 (SD, 26.6)|
|IPAA mean: 6.8 y (SD, 4.9 y)||IPAA: n = 118||IPAA: 84.4 (SD, 22.7)||IPAA: 42.2 (SD, 26.3)|
|88 Australian individuals (63 females and 25 males) aged 18–35 y, including 57 after colectomy and 14 with FAP but no surgery[
||Not reported||IRA: n = 33||Not assessed||Not assessed||SF-36 b||SF-36 b|
|IPAA: n = 21||IRA: 89.9 (SD, 16.1)||IRA: 86.2 (SD, 21.6)|
|Ileostomy: n = 1||IPAA: 72.1 (SD, 23)||IPAA: 77.5 (SD, 26.2)|
|Unknown surgery type: n = 2||No surgery: 94.1 (SD, 9.4)||No surgery: 91 (SD, 19)|
|525 individuals (283 females and 242 males) including 296 after colectomy, 45 with FAP but no surgery, 50 at risk for FAP and no surgery, and 134 noncarriers[
||Range: 0–1 y to >10 y||IRA: n = 136||Not assessed||Not assessed||EORTC QLQ-CR38 a||EORTC QLQ-CR38 a||41% of FAP patients reported employment disruptions:|
|After colectomy: 85.4 (SD, 20.5)||After colectomy: 42.2 (SD, 23.2)||Part or complete disability: n = 73 (59%)|
|IPAA: n = 112||FAP no surgery: 91.9 (SD, 16.1)||After colectomy: 42.2 (SD, 23.2)||Worked less: n = 30 (24%)|
|Ileostomy: n = 42||At risk: 94.0 (SD, 13.1)||At risk: 47.6 (SD, 23.7)||Worked more n = 5 (4%)|
|Other: n = 6||Noncarrier: 92.3 (SD, 13.1)||Noncarrier: 45.7 (SD, 21.2)||Worked more or less at different periods: n = 16 (13%)|
|209 Swedish FAP-affected individuals (116 females and 93 males) after colectomy aged 18–75 y[
||Mean time since last surgery: 14 y (SD, 10; range, 1–50 y)||IRA: n = 71||Not assessed||Day: 71% (n = 149)||Not assessed||Not assessed||The mean number of 21 abdominal symptoms assessed was 7 (SD, 4.61; range, 1–18). Women reported more symptoms than men, but there were no differences between genders regarding the degree the symptoms were troublesome. Higher symptom number was an independent predictor of poorer physical and mental health|
|IPAA: n = 82|
|Ileostomy: n = 39||Night: 61% (n = 128)|
|Continent ileostomy: n = 14|
|Other: n = 3|
|28 individuals (10 females and 18 males) who underwent colectomy at age 14 y or younger[
||12 y (SD, 8.4; range, 1–37 y)||IRA: n = 7||Day:||Day:||Rosenberg self-esteem score : 25.53/30c||Not assessed||10/28 reported cancer-related worry post colectomy, with a trend that young age (<18 y) was associated with more cancer-related worry|
|IRA: 3.8 (SD, 1.5)||IRA: 71.4% (n = 7)|
|IPAA: 5.3 (SD, 2.4)||IPAA: 85.7% (n = 21)|
|IPAA: n = 21||Night:||Night:|
|IRA: 1.3 (SD, 0.6)||IRA: 50.0% (n = 7)|
|IPAA: 1.3 (SD, 0.5)||IPAA: 61.9% (n = 21)|
Studies of risk-reducing surgery for FAP have found that general measures of quality of life have been within normal range, and the majority reported no negative impact on their body image. However, these studies suggest that risk-reducing surgery for FAP may have negative quality-of-life effects for at least some proportion of those affected.
Chemoprevention trials are currently under way to evaluate the effectiveness of various therapies for individuals at risk of Lynch syndrome and FAP.[
Reproductive Considerations in Individuals With Lynch Syndrome or FAP
Assisted reproductive technology (ART)
The possibility of transmitting a pathogenic variant to a child may pose a concern to families affected by hereditary CRC syndromes to the extent that some carriers may avoid childbearing. These concerns also may prompt individuals to consider using prenatal diagnosis (PND) methods to help reduce the risk of transmission. PND is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling.[
An alternative to these tests is preimplantation genetic testing (PGT), a procedure used to test fertilized embryos for genetic disorders before uterine implantation.[
From the limited studies published to date, there appears to be interest in the use of ART for FAP, Lynch syndrome, and PJS.[
|Study Population||Nc||Interest or Intention in ART||Comments|
|GT = genetic testing; PGT = preimplantation genetic testing; PND = prenatal diagnosis.|
| a Studies used a cross-sectional design and were conducted in the United States,[
|b Participants were invited to complete questionnaires before clinical genetic testing for Lynch syndrome and at 3 months and 1 year after disclosure of genetic test results.|
|c Indicates number of participants older than 18 y, unless otherwise specified.|
|d Total number of individuals with anAPCpathogenic variant. Not all individuals answered or were eligible to answer each question.|
| e Represents the number who indicated that they were considering having children in the future, out of a total of 130 individuals who answered a questionnaire before genetic testing.[
|f Total number of individuals with a Lynch syndrome pathogenic variant. Not all individuals answered or were eligible to answer each question.|
||20||95% (19/20) would consider prenatal GT for FAP; 90% (18/20) would consider PGT; 75% (15/20) would consider amniocentesis or chorionic villous sampling|
||341||33% (16/64) would consider PND for FAP; 30% (76/256) would consider PGT; 15% (52/341) felt terminating pregnancy for FAP was acceptable||24% and 25% of patients did not respond to questions about attitudes toward PND and PGT, respectively|
|Individuals with anAPCpathogenic variant associated with FAP[
||65d||25% (16/64) were aware of PGT; 78% (50/64) thought PGT should be offered; 55% (31/56) would consider PGT|
|Individuals undergoing genetic testing for Lynch syndrome[
||48e||21% 10/48) would consider PND and/or PGT; 19% (9/48) would consider only PND; 2% (1/48) would consider only PGT||At 1 year after disclosure of GT results, two of nine carriers reported that they were considering PGT for future pregnancy|
|Individuals with an identified Lynch syndrome pathogenic variant[
||43f||19% (8/42) were aware of PGT; 69% (29/42) thought PGT should be offered; 41% (16/39) would consider PGT|
||52||15% (8/52) indicated that pregnancy termination was acceptable if PND identified a fetus with PJS; 52% (27/52) indicated PGT was acceptable for individuals with PJS||Ten (19%) individuals, nine of whom were female, reported that they had decided not to conceive a child because of PJS|
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 American Cancer Society (Cancer Facts and Figures 2022) as reference 1.
Major Genetic Syndromes
Revised text to state that the median age of CRC diagnosis was 66 years in individuals with sporadic CRC (cited American Cancer Society [Colorectal Cancer Facts and Figures 2020–2022] as reference 370).
Updated National Comprehensive Cancer Network (NCCN) (Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic) as reference 581.
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 colorectal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Colorectal Cancer are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
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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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The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Colorectal Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389505]
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Last Revised: 2022-04-12
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