Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
Major Genetic Syndromes
Introduction
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).
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)
Introduction
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.[11] Classic FAP is characterized by numerous (hundreds to thousands) adenomatous polyps in the colon and rectum developing after the first decade of life (refer to Figure 3).
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.[1,12,13] It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births.[14] The presence of ethnic differences in the prevalence of FAP has been suggested [14] but a large study did not find significant differences in ethnic variation in more than 6,169 individuals with a personal and/or family history of CRC and polyps who were referred for genetic testing at a large reference laboratory.[15] Most cases of FAP result from pathogenic variants in the APC gene on chromosome 5q21. (Refer to the Genetics of FAP section of this summary for more information about the APC gene and genetic testing.)
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.
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.[23]
Clinical phenotype
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%.[1,12,13] The age at onset of adenomas in the colon is variable, and the median age for the appearance of colorectal adenomas is 16 years.[24] By age 10 years, only 15% of carriers of the APC germline variant manifest adenomas; by age 20 years, the probability rises to 75%; and by age 30 years, 90% will have presented with FAP.[1,12,13,24,25] The exception is AFAP, in which affected individuals typically have fewer colon polyps, which are predominantly in the right colon, and later onset of CRC. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.) Without any intervention, most individuals with FAP will develop CRC by the fourth decade of life.[1,12,13] Thus, surveillance and intervention for carriers of an APC pathogenic variant and at-risk persons have conventionally consisted of annual colonoscopy beginning around puberty for early detection of colonic polyps and to help plan when to perform colectomy.[26,27] (Refer to the Interventions for FAP section of this summary for more information.)
Extracolonic manifestations
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 [28,29] compared with a general population frequency of 1.2%.[30] The lesions are often present at birth or in early childhood and are frequently multiple or bilateral in FAP patients.[31] A study of 17 individuals diagnosed with FAP and 13 at-risk family members reported a sensitivity of the presence of a CHRPE lesion in association with colonic polyps in FAP of 76%, a specificity of 92%, a positive predictive value of 93%, and a negative predictive value of 75%; thus, screening at-risk individuals for CHRPE can be a reasonable method of detecting FAP.[28]
Desmoid tumors
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.[32] Desmoids may occur sporadically, as part of classical FAP, or in a hereditary manner without the colon findings of FAP.[19,33] Desmoids have been associated with hereditary APC pathogenic variants even when not associated with typical adenomatous polyposis of the colon.[33,34]
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.[33,35,36] APC pathogenic variants occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[34,37-39] Desmoid tumors with a late onset and a milder intestinal polyposis phenotype (hereditary desmoid disease) have been described in patients with pathogenic variants at codon 1924.[33]
A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors.[40] The desmoid risk factor scale was based on gender, presence or absence of extracolonic manifestations, family history of desmoids, and genotype, if available. By utilizing this scale, it was possible to stratify FAP patients into low-, medium-, and high-risk groups for developing desmoid tumors. The authors concluded that the desmoid risk factor scale could be used for surgical planning. Validation of the risk factors comprising this scale was supported by a large, multiregistry, retrospective study from Europe.[41]
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.[42] It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly.[43] Desmoids often occur after surgical or physiological trauma, and both endocrine and genetic factors have been implicated. Approximately 80% of intra-abdominal desmoids in FAP occur after surgical trauma.[44,45]
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.[36] In some series, desmoids are the second most common cause of death after CRC in FAP patients.[46,47] A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity.[48] The proposed staging system for intra-abdominal desmoids is as follows: stage I for asymptomatic nongrowing desmoids; stage II for symptomatic nongrowing desmoids of 10 cm or less in maximum diameter; stage III for symptomatic desmoids of 11 cm to 20 cm or for asymptomatic slow-growing desmoids; and stage IV for desmoids larger than 20 cm, or rapidly growing, or with life-threatening complications.[48]
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.[35,43,49]
Stomach tumors
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.[20,22,50-54] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[55,56]
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.[22,57] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs.[56] In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, FGPs were detected in 88% of the patients. Low-grade dysplasia was detected in 38% of these patients, whereas high-grade dysplasia was detected in 3% of these patients. The study's authors recommended that, if a polyp with high-grade dysplasia is identified, polypectomy be considered with repeat endoscopic surveillance in 3 to 6 months.[58]
Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs).[56,59] FGPs in this setting commonly show a PPI effect consisting of congestion of secretory granules in parietal cells, leading to irregular bulging of individual cells into the lumen of glands. To the trained eye, the presence of dysplasia and the concomitant absence of a characteristic PPI effect can be considered highly suggestive of the presence of underlying FAP. The number of FGPs tends to be greater in FAP than that seen in patients consuming PPIs, although there is some overlap.
Gastric adenomas also occur in FAP patients. The incidence of gastric adenomas in Western patients has been reported to be between 2% and 12%, whereas in Japan, it has been reported to be between 39% and 50%.[60-63] These adenomas can progress to carcinoma. FAP patients in Korea and Japan are reported to have a threefold to fourfold increased risk of gastric cancer compared with the general population in those countries, a finding not observed in Western populations.[64-68] One potential explanation for a higher prevalence of gastric adenomas in Asian FAP patients than that seen in Western FAP patients may be the higher overall prevalence of Helicobacter pylori infection.[61]
More recently, a rise in incidence of gastric adenocarcinoma was observed in a Western FAP database.[69] Alterations in the promoter (1B) of APC were discovered in families with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), who express numerous, predominantly fundic gland, gastric polyps restricted to the body and fundus with regions of dysplasia or gastric adenocarcinoma, and no evidence of colorectal or duodenal polyposis. These variants segregated with the gastric phenotype in multiple GAPPS families. Although penetrance of the gastric polyposis phenotype is high, the phenotype can vary ranging from asymptomatic adults to teenagers presenting with massive symptomatic gastric polyposis, as well as unaffected carriers who had clean endoscopies at ages ranging from 42 to 77 years. However, the penetrance for gastric cancer is less clear. Promoter 1B APC alterations rarely occur in FAP families with gastric fundic gland polyps and colonic polyposis.[70]
Duodenum/small bowel tumors
Whereas the incidence of duodenal adenomas is only 0.4% in unselected patients undergoing upper GI endoscopy,[71] duodenal adenomas are found in 80% to 100% of FAP patients. Most are located in the first and second portions of the duodenum, especially in the periampullary region.[50,51,72] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[17,66,73,74] In a prospective multicenter surveillance study of duodenal adenomas in 368 participants from northern Europe with FAP, 65% had adenomas at baseline evaluation (mean age, 38 y), with cumulative prevalence reaching 90% by age 70 years. In contrast to earlier beliefs regarding an indolent clinical course, the adenomas increased in size and degree of dysplasia during the 8 years of average surveillance, although only 4.5% developed cancer while under prospective surveillance.[20] This is a large study; however, it is limited by the use of forward-viewing rather than side-viewing endoscopy and the large number of investigators involved in the study. Intestinal polyps can also be assessed in FAP patients using capsule endoscopy.[75-77] One study of computed tomography (CT) duodenography found that larger adenoma size could be accurately measured but smaller, flatter adenomas could not be accurately counted.[78]
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.[79] A decision analysis of 601 FAP patients suggested that the benefit of periodic surveillance starting at age 30 years led to an increased life expectancy of 7 months.[73] Although polyps in the duodenum can be difficult to treat, small series suggest that they can be managed successfully with endoscopy but with potential morbidity—primarily from pancreatitis, bleeding, and duodenal perforation.[80,81]
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.[20,74,82,83] Because the risk of duodenal adenocarcinoma is correlated with the number and size of polyps and the severity of dysplasia of the polyps, a stratification system that incorporates these features was developed to attempt to identify those individuals with FAP at the highest risk of developing duodenal adenocarcinoma.[83] According to this system, known as the Spigelman classification (refer to Table 5), 36% of patients with the most advanced stage will develop carcinoma.[74]
Other tumors
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.[84] However, a study [85] of papillary thyroid cancers in six women with FAP failed to demonstrate loss of heterozygosity (LOH) or pathogenic variants of the wild-type allele in codons 545 and 1061 to 1678 of the six tumors. In addition, four of five of these patients had detectable somatic RET/PTC chimeric genes. This pathogenic variant is generally restricted to sporadic papillary thyroid carcinomas, suggesting the involvement of genetic factors other than APC pathogenic variants. Further studies are needed to show whether other genetic factors such as the RET/PTC chimeric gene are independently responsible for or cooperative with APC variants in causing papillary thyroid cancers in FAP patients.
Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH at the APC locus in an adrenocortical carcinoma (ACC) in an FAP patient.[86] In a study of 162 FAP patients who underwent abdominal CT for evaluation of intra-abdominal desmoid tumors, 15 patients (11 women) were found to have adrenal tumors.[87] Of these, two had symptoms attributable to cortisol hypersecretion. Three of these patients underwent subsequent surgery and were found to have ACC, bilateral nodular hyperplasia, or adrenocortical adenoma. The prevalence of an unexpected adrenal neoplasia in this cohort was 7.4%, which compares with a prevalence of 0.6% to 3.4% (P < .001) in non-FAP patients.[87] No molecular genetic analyses were provided for the tumors resected in this series. A subsequent study identified adrenal lesions in 26% (23 of 90) of patients with FAP, 18% (2 of 11) of patients with AFAP, and 24% (5 of 21) of patients with MAP. Most lesions in this series followed a benign and slowly progressive course; no cases of ACC were reported.[88]
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.[89-98] Some series have also demonstrated LOH of APC in these tumors.[90,92,99] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[100] (Refer to the Hepatoblastoma section in the PDQ summary on Childhood Liver Cancer Treatment for more information.)
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).[101]
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%.[101]
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.[102] Most of these changes are insertions, deletions, and nonsense variants that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC pathogenic variant (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other pathogenic variants appear to predominate. Variants that reduce rather than eliminate production of the APC protein may also lead to FAP.[103]
Genotype-phenotype correlations
Most APC pathogenic variants that occur between codon 169 and codon 1249 result in the classic FAP phenotype.[104-106] There has been much interest in correlating the location of the pathogenic variant within the gene with the clinical phenotype:
- Researchers have found that dense carpeting of colonic polyps, a feature of classic FAP, is seen in most patients with APC pathogenic variants, particularly those variants that occur between codons 1250 and 1464. AFAP is associated with pathogenic variants that occur in or upstream of exon 4 and in the latter two-thirds of exon 15.[104-107] (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.)
- CHRPE are rarely associated with pathogenic variants that occur before exon 9.[39,106] Individuals with exon 9 variants tend not to have duodenal adenomas.[70,108]
- Families with GAPPS, who express numerous, predominantly fundic gland gastric polyps restricted to the body and fundus with regions of dysplasia or gastric adenocarcinoma, and no evidence of colorectal or duodenal polyposis, were found to possess variants in the promoter (1B) of APC.[70]
- APC pathogenic variants occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[34,37-39]
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
Probands
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).[109] AFAP can be diagnosed by testing for germline APC pathogenic variants. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.) MAP is caused by biallelic germline pathogenic variants in the MUTYH gene, inherited in an autosomal recessive manner.[110] PPAP is caused by heterozygous pathogenic variants in POLE and POLD1.[111,112] BMMRD is a condition in which individuals inherit pathogenic variants in both alleles of one of the MMR genes (MLH1, MSH2, MSH6, PMS2, or EPCAM).[113] (Refer to the MUTYH-Associated Polyposis [MAP], Oligopolyposis, and Biallelic mismatch repair deficiency [BMMRD] sections of this summary for more information.)
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.[114] In this same study, the prevalence of biallelic MUTYH pathogenic variants was similar to APC for those with the attenuated phenotype (20–99 adenomas), but MUTYH pathogenic variants were also observed in a small minority (2%) of those with classic polyposis.[114]
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.[115-118] As mentioned, for patients who present with polyposis, multigene panels that include multiple polyposis genes are often ordered, which simplifies and lowers the cost of testing by assessing all genes at the same time. (Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Cascade testing
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.[119] In cases where the variant cannot be identified in leukocyte DNA of either parent, it is possible that germline mosaicism may explain the finding. Thus, siblings of an individual should always be offered APC testing, but testing aunts, uncles, and cousins of the proband would not be indicated.
The early appearance of clinical features of FAP and the subsequent recommendations for surveillance beginning at puberty raise special considerations relating to the genetic testing of minors.[120] In general, genetic testing of minors for hereditary cancer syndromes is not recommended unless the results are expected to inform medical management in childhood. Thus, FAP presents an example in which possible medical benefit justifies genetic testing of minors in families with a known pathogenic variant, especially for the anticipated 50% of at-risk children who will be found not to be carriers of pathogenic variants and who can thus be spared surveillance. In addition, testing infants for FAP can allow for hepatoblastoma surveillance until age 5 years. Otherwise, if at-risk minors are not tested, colonoscopy or flexible sigmoidoscopy is initiated between ages 10 to 15 years.[121] The psychological impact of such testing is addressed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary.
Interventions for FAP
Colon surveillance
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.[122] If feasible, the patient and his/her family members should be included in a registry because it has been shown retrospectively that registration and surveillance reduce CRC incidence and mortality.[123] In patients with classic FAP identified very early in their course, the surgeon, endoscopist, and family may choose to delay surgery for several years in the interest of achieving social milestones. In addition, in carefully selected patients with AFAP (those with minimal polyp burden and advanced age), deferring a decision about colectomy may be reasonable with surgery performed only in the face of advancing polyp burden or dysplasia.
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.[124] The study included 154 families with at least one family member clinically diagnosed with FAP from 1963 to 2015. There were 194 probands and 225 family members (83 diagnosed by genetic testing and 142 by endoscopy) with a median time of follow-up of 11.8 years. In this study, the survival analysis of members of FAP families was calculated using the relative survival estimate.[125] This estimation compares survival among FAP probands and family members with the survival expected in the absence of FAP among individuals of the same gender and age in each calendar year. The relative survival for probands was 67% (95% CI, 60%–75%) after 10 years of follow-up and 66% (95% CI, 58%–76%) after 20 years. For family members, the relative survival was 98% (95% CI, 95%–101%) at 10 years and 94% (95% CI, 88%–100%) at 20 years. At 25 years of follow-up, the relative survival for family members was lower than the general population at 87% (95% CI, 79%–96%). The relative survival was significantly lower for probands than for family members (P < .001). In terms of mortality, the standardized mortality ratio was elevated in probands in both the 0- to 5-year and 5- to 10-year periods of follow-up whereas it remained stable for family members until 20 years of follow-up. This difference was more marked in the beginning of follow-up for probands taking into account the fact that probably most were symptomatic, and most likely had CRC at the diagnosis. The authors pointed out that if the CRC was treated successfully without recurrence, the survival of the probands approached that of the family members.
Endoscopic surveillance usually begins early (age, 10–15 y).[121] (Refer to the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for more information on the social and emotional implications of early surveillance.) Historically, sigmoidoscopy may have been a reasonable approach in identifying early adenomas in most patients. However, colonoscopy is the tool of choice in light of (a) improved instrumentation for full colonoscopy; (b) sedation; (c) recognition of AFAP, in which the disease is typically most manifest in the right colon; and (d) the growing tendency to defer surgery for a number of years.[121] Individuals who have tested negative for an otherwise known family pathogenic variant do not need FAP-oriented endoscopic surveillance; they are recommended by NCCN to undergo average-risk population screening. In the case of families in which no family variant has been identified in an affected person, clinical surveillance is warranted. Colon surveillance is not stopped in persons who are known to carry an APC pathogenic variant but who do not yet manifest polyps, because adenomas occasionally are not manifest until the fourth and fifth decades of life. (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)
Colorectal surgery
Colon adenomas will develop in nearly 100% of persons 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.[126] Once numerous polyps have developed, surveillance colonoscopy is no longer useful in timing the colectomy because polyps are so numerous that it is not possible to biopsy or remove all of them. At this time, it is appropriate for patients to consult with a surgeon who is experienced with available options, including total colectomy and restorative proctocolectomy.[127] Rectum-sparing surgery, with sigmoidoscopic surveillance of the remaining rectum, is a reasonable alternative to total colectomy in those compliant individuals with relative rectal sparing of polyps who understand the consequences and make an informed decision to accept the residual risk of rectal cancer occurring despite periodic surveillance.[128]
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%.[129,130] This risk has been reported to be much lower with better selection of patients for IRA.[127,131] Factors that have been reported to increase rectal cancer risk after IRA include the number of polyps throughout the colon, the number of polyps in the rectum, the presence of colon cancer at the time of IRA, the length of the rectal stump, the duration of follow-up after IRA, and the genotype.[39,132-134] An abdominal colectomy with IRA as the primary surgery for FAP does not preclude later conversion to an IPAA for uncontrolled rectal polyps and/or rectal cancer. In the Danish Polyposis Registry, the morbidity and functional results of a secondary IPAA (after a previous IRA) in 24 patients were reported to be similar to those of 59 patients who underwent primary IPAA.[135]
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.[136] In some cases, however, the polyp burden is equivocal, and in such cases, investigators have considered the role of genotype in predicting subsequent outcomes with respect to the rectum.[137] Pathogenic variants reported to increase the rectal cancer risk and eventual completion proctectomy after IRA include variants in exon 15 codon 1250, exon 15 codons 1309 and 1328, and exon 15 variants between codons 1250 and 1464.[138,129,139,140] 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.[141,142] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[143] A meta-analysis of quality of life after restorative proctocolectomy and IPAA has suggested that patients with FAP do marginally better than patients with inflammatory bowel disease in terms of fistula formation, pouchitis, stool frequency, and seepage.[144]
Chemoprevention
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.[145,146] Although celecoxib had been approved by the U.S. Food and Drug Administration (FDA), its license was voluntarily withdrawn by the manufacturer. Currently, there are no FDA-approved drugs for chemoprevention in FAP. Nevertheless, agents such as celecoxib and sulindac are in sufficiently widespread use that chemopreventive clinical trials typically utilize one of these agents as the control arm. A randomized trial showed possible marginal improvement in polyp burden with the combination of celecoxib and difluoromethylornithine, compared with celecoxib alone.[147]
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.[148] This study found a dose-dependent reduction in adenomatous polyp burden. At a dose of 16 mg/kg/day, which approximates the approved dose of 400 mg twice daily in adults, the reduction in polyp burden paralleled that demonstrated with celecoxib in adults.
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.[149] Although not directly compared in a randomized trial, the effect appeared to be similar in magnitude to that previously observed with celecoxib.
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.[146]
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.[150] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[151] The same issues surrounding the use of COX-2 inhibitors for the treatment of colonic polyps apply to their use for the treatment of duodenal polyps (e.g., only partial elimination of the polyps, complications secondary to the COX-2 inhibitors, and loss of effect after the medication is discontinued).[150]
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,[152] two trials that employ ursodeoxycholate have been performed.[153,154] In both studies, ursodeoxycholate did not have a significant chemopreventive effect on duodenal polyps; paradoxically, in one study, ursodeoxycholate in combination with celecoxib appeared to promote polyp density in patients with FAP.
Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[155-157] it is unclear whether this class of agents will be safe for long-term use for patients with FAP and in the general population. Also, because of the short-term (6 months) nature of these trials, there is currently no clinical information about cardiac events in FAP patients taking COX-2 inhibitors on a long-term basis.
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.[158]
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% [159] suggesting that EGFR inhibitors had the potential to inhibit duodenal polyps in FAP patients. A 6-month double-blind, randomized, placebo-controlled trial tested the efficacy of sulindac, 150 mg twice daily, and erlotinib, 75 mg daily, versus placebo in FAP or AFAP patients with duodenal polyps.[160] Ninety-two patients with FAP or AFAP were randomly assigned to receive study drugs or placebo and underwent pretreatment and posttreatment upper endoscopies to determine the changes in the sum diameter of the polyps and number of polyps in a 10 cm segment of proximal duodenum. The trial was terminated prematurely because the primary endpoint was met. The intent-to-treat analysis demonstrated a median decrease in duodenal polyp burden (sum of diameters) of 8.5 mm in the sulindac/erlotinib arm while there was an 8 mm increase in the placebo arm (P < .001). Significantly higher rates of grade 1 and grade 2 adverse events occurred in the treatment arm than in the placebo arm: in the treatment arm, 60.9% developed an acneiform rash and 32.6% developed oral mucositis; in the placebo arm, 19.6% developed an acneiform rash and 10.9% developed oral mucositis. On the basis of the previously modest effects of sulindac and celecoxib on duodenal polyps in FAP patients [146,158] and the dramatic effect of genetic EGFR inhibition on intestinal adenoma development in the Apcmin/+ mouse,[161] it is likely that erlotinib was responsible for the success of this trial. An ongoing clinical trial is determining whether lower doses of erlotinib alone are sufficient for significantly reducing duodenal polyp burden in FAP and AFAP patients.
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.
Desmoid tumors
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.[162-164]
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.[162] Six patients had been on tamoxifen or sulindac before treatment with raloxifene, and seven patients were previously untreated. All 13 patients with intra-abdominal desmoid disease had either a partial or a complete response 7 months to 35 months after starting treatment, and most desmoids decreased in size at 4.7 months (± 1.8 mo) after treatment. Response occurred in patients with desmoid plaques and with distinct lesions. Study limitations include small sample size and the clinical evaluation of response, which was not consistent in all patients. Several questions remain concerning the outcomes of patients with desmoid tumors not expressing estrogen-alpha receptors who have received raloxifene, as well as which patients may benefit from this potential treatment.
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.[163] These results suggest that the combination of these agents may be effective in slowing the growth of desmoid tumors. However, the natural history of desmoids is variable, with both spontaneous regression and variable growth rates.
A third study reported mixed results in 14 patients with FAP-associated desmoid tumors treated with pirfenidone for 2 years.[164] In this study, some patients had disease regression, some patients had disease progression, and some patients had stable disease.
There are reports of using imatinib mesylate to treat desmoid tumors in FAP patients with some success.[165,166] Nilotinib demonstrated potential to stabilize desmoid tumor growth after treatment failure with imatinib in patients with desmoid tumors.[167]
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.[168] Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression on the placebo arm of the study. Objective responses were demonstrated in 16 of 49 patients treated with sorafenib (33%) compared with 7 of 35 placebo-treated patients (20%). Additionally, the two-year progression-free survival (PFS) rate was significantly higher for sorafenib (81%) than placebo (36%); the hazard ratio for progression or death was 0.13 (95% CI, 0.05–0.31; P < .001). The most frequently reported adverse events were grade 1 or grade 2 rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). Despite a relatively favorable toxicity profile, approximately 20% of patients discontinued sorafenib due to toxicity, emphasizing the importance of appropriate dose delays and interruptions for the treatment of adverse events.
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.[169,170] Issues of subject selection are critical in evaluating surgical outcome data.[169] Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.
Stomach tumors
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.[171,172] More recently, a rise in incidence of gastric adenocarcinoma was observed in a Western FAP database [69] suggesting that a possible change in the management of gastric tumorigenesis in FAP may be in order. One group recommends endoscopic polypectomy for the management of gastric adenomas.[69] The management of adenomas in the stomach is usually individualized on the basis of the size of the adenoma and the degree of dysplasia.
Duodenum/small bowel tumors
A baseline upper endoscopy, including side-viewing duodenoscopy, is typically performed between ages 25 and 30 years in FAP patients.[67] The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy, often based on Spigelman stage. Recommended intervals are based on expert opinion although the relatively liberal intervals for stage 0 to stage II disease are based in part on the natural history data generated by the Dutch/Scandinavian duodenal surveillance trial (refer to Table 6 for available recommendations regarding screening frequency by Spigelman stage).[20]
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.[63,173] However, the following are limitations of application of the Spigelman classification:
- Most pathologists do not employ the term moderate dysplasia, preferring a simpler low- versus high-grade dysplasia system.
- Because of the villous nature of normal duodenal epithelium, pathologists commonly disagree over the classification of tubular, tubulovillous, and villous.
- Spigelman staging requires biopsy, which is not always essential when only a few small plaques are present; conversely, for larger adenomas, sampling variation leads to understaging.[174,175]
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.[177] According to the protocol, biennial frontal-viewing endoscopy was performed from 1990 through 2000. Subsequently, patients were followed up with surveillance according to international guidelines. The study group comprised 261 of 304 patients (86%) who had more than one endoscopy. Median follow-up was 14 years (range, 9–17 y). The lifetime risk of duodenal adenomatosis was 88%. Forty-four percent of patients had worsening Spigelman stage over time, whereas 12% improved and 34% remained unchanged. Twenty patients (7%) developed duodenal cancer at a median age of 56 years (range, 44–82 y). The cumulative cancer incidence was 18% at age 75 years (95% CI, 8%–28%). Survival in patients with symptomatic cancers was worse than those diagnosed at surveillance endoscopy.
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;[80,81,178] however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum.[174] The most definitive procedure for reducing the risk of adenocarcinoma is surgical resection of the ampulla and duodenum, although these procedures also have higher morbidity and mortality associated with them than do endoscopic treatments. Duodenotomy and local resection of duodenal polyps or mucosectomy have been reported, but invariably, the polyps recur after these procedures.[179] In a series of 47 patients with FAP and Spigelman stage III or stage IV disease who underwent definitive radical surgery, the local recurrence rate was reported to be 9% at a mean follow-up of 44 months. This local recurrence rate was dramatically lower than any local endoscopic or surgical approach from the same study.[174] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[175,179-181] If such surgical options are considered, preservation of the pylorus is of particular benefit in this group of patients because most will have undergone a subtotal colectomy with IRA or total colectomy with IPAA. As noted in a Northern European study,[20] and others,[182,183] most patients with duodenal adenomas will not develop cancer and can be followed with endoscopy. However, individuals with advanced adenomas (Spigelman stage III or stage IV disease) generally require endoscopic or surgical treatment of the polyps. Chemoprevention studies for duodenal adenomas in FAP patients are under way and may offer an alternate strategy in the future. (Refer to the Chemoprevention section of this summary for more information.)
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.[81,174,175,180,184-187] The literature uniformly supports duodenectomy for Spigelman stage IV disease. For Spigelman stage II and stage III disease, there is a role for endoscopic treatment invariably focusing on the one or two worst lesions that are present.
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,[174,175,181,184,188-194] fear of surgical intervention can lead to aggressive and somewhat ill-advised endoscopic interventions. In some circumstances, endoscopic resection of ampullary and/or other duodenal adenomas cannot be accomplished completely or safely by endoscopic means, and duodenectomy cannot be accomplished without risking a short-gut syndrome or cannot be done at all because of mesenteric fibrosis. In such cases, surgical transduodenal ampullectomy/polypectomy can be performed. However, this is associated with a high risk of local recurrence similar to that of endoscopic treatment.
Other tumors
Although level 1 evidence is lacking, a consensus opinion recommends annual thyroid examinations beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP. The same panel suggests clinicians could consider the addition of annual thyroid ultrasonography to this screening routine.[121,195,196]
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.[121,197] It is not necessary to continue screening after age 5 years.
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 the diagnosis of 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.[101]
Attenuated Familial Adenomatous Polyposis (AFAP)
Clinical phenotype
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.[198] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[199] Adenomas in AFAP are believed to form around the age of mid-twenties to late twenties.[57] Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years.[104,105,200] Affected family members have developed CRCs with very few synchronous polyps.[2] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (FGPs, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoid tumors.[57] Because of the specific sites of APC pathogenic variants causing AFAP, these patients typically lack CHRPE lesions.
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:[104-107,201,202]
- Pathogenic variants associated with the 5’ end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper GI polyps. Any pathogenic variant in the first four exons,[104] as there is an internal ribosomal entry site in exon 4 that permits the ribosome to skip premature truncation pathogenic variants.[203]
- Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
- 3’ region pathogenic variants in which patients have very few adenomas (<50).
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.
Clinical management
Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[204,205] The role for and timing of risk-reducing colectomy in AFAP is controversial.[206]
Table 7 summarizes the clinical practice guidelines from different professional societies regarding surveillance of AFAP.
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.[208] The protein encoded by MUTYH is a base excision repair glycosylase, which repairs one of the most common forms of oxidative damage. Over one hundred unique sequence variants of MUTYH have been reported (Leiden Open Variation Database). A founder pathogenic variant with ethnic differentiation is assumed for MUTYH pathogenic variants. In white populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic pathogenic variants in MAP patients; 90% of these patients carry at least one of these pathogenic variants.[209] Other causative variants that have been found include P405L (formerly known as P391L) (Netherlands),[210,211] E480X (India),[212] Y104X (Pakistan),[213] 1395delGGA (Italy),[214,215] 1186-1187insGG (Portugal),[216] and p.A359V (Japan and Korea).[217-219]
The MUTYH gene was first linked to polyposis in 2002 in three siblings with multiple colonic adenomas and CRC but no APC pathogenic variant.[110] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and Lynch syndrome.[220] MAP patients tend to develop fewer adenomas at a later age than patients with APC pathogenic variants [221,222] but still carry a high risk of CRC (35%–75%).[7,223,224] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MUTYH pathogenic variants of 4% (95% CI, 3%–5%) among those with 10 to 19 adenomas, 7% (95% CI, 6%–8%) among those with 20 to 99 adenomas, and 7% (95% CI, 6%–8%) among those with 100 to 999 adenomas.[114] This broad clinical presentation results from the MUTYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with an FAP phenotype and without a detectable APC germline pathogenic variant carry biallelic variants in the MUTYH gene.[7,212,222,225]
Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients.[226] The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[208] Clinical management guidelines for MAP range between once a year to every 3 years for colonoscopic surveillance beginning at age 18 to 30 years,[121,207,223] with upper endoscopic surveillance beginning at age 25 to 30 years.[207] (Refer to Table 8 for more information about available clinical practice guidelines for colon surveillance in MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria.[207] Total colectomy with ileorectal anastomosis or subtotal colectomy may be necessary for patients with MUTYH-associated polyposis depending on overall polyp burden.[223,227]
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.
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).[228,229] Additionally, noncancerous extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[214,222,229,230] Female MAP patients have an increased risk of breast cancer.[231] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or Lynch syndrome.[232,233]
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%.[229]
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.[234] Of 92 patients, 31 (34%) had evidence of duodenal polyps. The median age at duodenal adenoma detection was 50 years, and in 65% of patients duodenal adenomas were diagnosed at baseline endoscopy. Eighty-four percent of patients had Spiegelman stage I or stage II polyposis at first detection of polyps, with no patients with stage IV polyposis and no high-grade dysplasia detected. In subsequent surveillance only two patients progressed to Spiegelman stage IV polyposis, after 3.6 and 7.0 years, respectively. There additionally appeared to be sparing of the ampulla, with only two individuals having diminutive polyps without dysplasia in the ampulla. No cancers were detected in patients enrolled in upper GI surveillance programs within these registries. Two individuals with MAP were diagnosed with ampullary and duodenal cancer respectively at ages 83 and 63 years at the time of first-ever upper GI endoscopies. Therefore, duodenal polyps appear less prevalent in MAP compared with FAP, and appear at a later age. On the basis of these results, the authors suggest upper GI endoscopic screening in MAP be initiated at age 35 years.
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.[7,110,222] A 2011 meta-analysis found that carriers of monoallelic MUTYH pathogenic variants are at modestly increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98–1.36); however, given the rarity of carriers of monoallelic pathogenic variants, they account for only a trivial proportion of all CRC cases.[235] A large study of 2,332 heterozygotes among 9,504 relatives of 264 CRC cases with a MUTYH pathogenic variant found that the risk of CRC at age 70 years was 7.2% for men and 5.6% for women, irrespective of family history. Among those with an FDR with a CRC diagnosis before age 50 years, the risk at age 70 years was 12.5% for men and 10% for women.[224] Caution should be exercised in the interpretation of this study as the vast majority of carrier status from this study was imputed and not based on genotype. The authors felt the risk for MUTYH heterozygotes with an FDR with CRC was sufficiently high to warrant more intensive surveillance than the general population (but the same as for anyone with an FDR with CRC diagnosed before age 50 y).[221,224]
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).[236] However, a German study failed to duplicate these findings.[237] Additionally, a larger study found no increased cancer risk for carriers of MMR pathogenic variants with a MUTYH variant compared with those with a MMR pathogenic variant alone.[238]
Oligopolyposis
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.[239] However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC pathogenic variant. The lower the polyp count the lower the probability of having an APC pathogenic variant. Some of these cases are now known to carry biallelic MUTYH pathogenic variants or variants in other genes linked to oligopolyposis.[240]
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).[241,242] An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative (FDR) with CRC. All had negative APC, MUTYH, and MMR gene pathogenic variant test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant.
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.[243] All individuals in this study were negative for germline pathogenic variants in APC, MUTYH, and the MMR genes. The POLE variant L424V was found in 3 of 485 index cases with colorectal polyposis and early-onset CRC. Tumors showed microsatellite instability (MSI) and were deficient of one or more MMR proteins in two of three index cases. Somatic mutations in MMR genes, possibly the result of hypermutability secondary to POLE deficiency, were detected in these two cases. The Cancer Genome Atlas Network performed extensive sequencing analysis of 276 CRCs, and found that the presence of somatic mutations in the POLE gene was associated with a hypermutated phenotype with a substantially greater mutational burden than present in CRCs with MSI. Thus, polymerase variants appear to generate an ultra-hypermutated genotype in the tumor.[244]
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.[245] These individuals had CRC, multiple adenomas (8–50), none of which were either hyperplastic or serrated, and in three affected females, there was either endometrial cancer or endometrial complex hyperplasia. There were two other individuals who developed duodenal adenomas and duodenal cancer. All pedigrees were consistent with autosomal recessive inheritance. Upon examining three cancers and five adenomas from different affected individuals, none showed MSI. These neoplasms did show enrichment of cytosine to thymine transitions. Additional studies are needed to further define the phenotype. A subsequent study of 863 families with CRC and 1,600 families without CRC confirmed an association between biallelic NTHL1 pathogenic variants and inherited CRC risk.[246] Currently, there is no known increased risk of cancer for individuals harboring a single monoallelic pathogenic germline NTHL1 variant.
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.[247-249] Consequently, such patients are increasingly being referred for genetic counseling and for consideration of genetic testing. Occasional cases of MUTYH biallelic pathogenic variants have been found in patients with at least some features of serrated polyposis and serrated polyps can be seen in Lynch syndrome. However, germline evaluation of individuals with serrated polyposis is typically unrevealing.[250-254]
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.[255,256] This phenomenon, termed therapy-associated polyposis (TAP), may be an acquired, nonfamilial phenotype caused by prior antineoplastic therapy, and is on the differential diagnosis when nonfamilial oligopolyposis is identified in individuals previously treated with chemotherapy and/or radiation. Another recent study identified oligopolyposis fulfilling WHO criteria for serrated polyposis syndrome (SPS) in 6% of a cohort of 101 Hodgkin lymphoma survivors treated with prior chemotherapy and/or radiation therapy, suggesting that Hodgkin lymphoma survivors may be a particularly important population in whom TAP can manifest.[257]
Lynch Syndrome
Introduction
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.[258]
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.[259] The Amsterdam criteria were originally used for the identification of high-risk families and included fulfillment of all of the following: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50 years, and no evidence of FAP.
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,[260] from which the APC gene was eventually cloned in 1991.[261] This led to searches for similar linkage in families suspected of having Lynch syndrome who had multiple cases of CRC inherited in an autosomal dominant fashion and young onset of cancer development. The APC gene was one of several genes (along with DCC and MCC) evaluated in families that fulfilled Amsterdam criteria, but no linkage was found among the Lynch kindreds. In 1993, an extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large families. Once MSH2, the first Lynch syndrome–associated gene, was sequenced, it was evident from the somatic mutation patterns in the CRC tumors that the MMR family of genes was likely involved. Additional MMR genes were subsequently linked to Lynch syndrome, including MLH1, MSH6, and PMS2. Lynch syndrome now refers to the genetic disorder caused by a germline variant in one of these DNA MMR genes, distinguishing it from other familial clusters of CRC.
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.[259] These research criteria were limited to diagnoses of familial CRC. In 1999, the Amsterdam criteria were revised to include some extracolonic cancers, predominantly endometrial cancer.[262] These criteria provide a general approach to identifying Lynch syndrome families, but they are not considered comprehensive; nearly half of families meeting the Amsterdam criteria do not have detectable pathogenic variants.[263]
Amsterdam criteria I (1990):
- One family member diagnosed with CRC before age 50 years.
- Two affected generations.
- Three affected relatives, one of them an FDR of the other two.
- FAP should be excluded.
- Tumors should be verified by pathological examination.
Amsterdam criteria II (1999):
- Same as Amsterdam criteria I, but tumors of the endometrium, small bowel, ureter, or renal pelvis can be used to substitute an otherwise qualifying CRC.
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.[264,265] (Refer to the Genetic and molecular testing for Lynch syndrome section of this summary for more information about testing for MSI and IHC.)
Bethesda guidelines (1997):
- Cancer in families that meet the Amsterdam criteria.
- The presence of two Lynch syndrome–related cancers, including synchronous and metachronous CRCs or associated extracolonic cancers. [Note: Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cell carcinoma of the renal pelvis or ureter.]
- The presence of CRC and a FDR with CRC and/or Lynch syndrome–related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed before age 45 years, and the adenoma diagnosed before age 40 years.
- CRC or endometrial cancer diagnosed before age 45 years.
- Right-sided CRC with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed before age 45 years. [Note: Solid/cribriform defined as poorly differentiated or undifferentiated carcinoma composed of irregular, solid sheets of large eosinophilic cells and containing small gland-like spaces.]
- Signet-ring–cell CRC diagnosed before age 45 years. [Note: Composed of more than 50% signet ring cells.]
- Adenomas diagnosed before age 40 years.
Revised Bethesda guidelines (2004)*:
- CRC diagnosed in an individual younger than 50 years.
- Presence of synchronous, metachronous colorectal, or other Lynch syndrome–associated tumors.**
- CRC with MSI-high (MSI-H) pathologic associated features diagnosed in an individual younger than 60 years. [Note: Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.]
- CRC or Lynch syndrome–associated tumor** diagnosed in at least one FDR younger than 50 years.
- CRC or Lynch syndrome–associated tumor** diagnosed at any age in two FDRs or second-degree relatives.
*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.[265,266]
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.[267] Furthermore, the Bethesda guidelines were not consistently used in clinical practice to identify the subset of individuals with CRC who should have MSI tumor testing; the guidelines were deemed cumbersome and difficult to remember by health care providers and the opportunity to refer for genetic evaluation was missed.[268]
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.[269-272]
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).[272]
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.[273-282] Deciding on which model to use in the risk assessment process depends on both the clinical setting in which it is applied and the patient population that is being evaluated. MMRpro’s predictions account for family size and unaffected relatives, the possibility of including molecular tumor data in the risk analysis, and the option of predicting pathogenic variant carrier status following germline testing. The major limitation in the widespread use of MMRpro in routine practice is the need to input data from the entire pedigree (including individuals without cancer), which is relatively time-consuming. Its best use is likely to be as a genetic counseling tool in a specialized high-risk clinic or research setting, as its accessibility is also limited. PREMM’s major advantages include that it is easy to use, available as an online tool, and has been extensively validated, including in a self-administered setting in a GI clinic.[283] It includes risk prediction based on personal and family cancer history up to second-degree relatives for a broad spectrum of extracolonic cancers. However, the model does not take into account family size and may overestimate the likelihood of a pathogenic variant in a pedigree that includes multiple elderly family members who are unaffected by CRC or endometrial cancer. Given the ease with which one can use the PREMM model (it has been deemed less time-consuming than MMRpro in validation studies),[278] it may be used by diverse health care providers whose primary aim is to identify patients who should be referred for genetic evaluation, and is likely to be most useful in the pretesting decision-making process. Lastly, MMRpredict’s use may be limited overall because of its less accurate risk estimates [284] when used to evaluate families with Lynch syndrome–associated cancers and older individuals affected by CRC; the model was developed using data from young-onset CRC cases (patients diagnosed at age <55 y) and did not include extracolonic malignancies. Furthermore, the model does not incorporate tumor testing results or provide post-hoc risk estimates based on gene sequencing results.
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.
Summary
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
MSI
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.[285,286] The term MSI is used when colorectal, endometrial, or metastatic tumor DNA [287] shows insertions or deletions in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic mutations, germline variants, or epigenetic alterations.[288] In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all tumors with MSI and not all tumors with loss of protein expression on IHC will be microsatellite unstable.
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.[289]
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.[290] The clinical relevance of MSI-L tumors remains controversial; the probability is very small that these tumors are associated with a germline pathogenic variant in an MMR gene.
The original Bethesda panel has been replaced by a pentaplex panel of five mononucleotide repeats,[290] which has improved the detection of MSI-H tumors.
(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
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) [287] for protein expression using monoclonal antibodies for the MLH1, MSH2, MSH6, and PMS2 proteins. Isolated loss of expression of any one of these proteins may suggest which specific MMR gene is altered in a particular patient.[291-294] However, certain proteins can form heterodimers (or have other binding partners) and yield loss of two proteins expressed on IHC.
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.[288,295] For example, MSH2 protein complexes with MSH6 protein to form MutSα, which has the main ability to repair single base pair mismatches and single base pair loop-out lesions that can occur during the replication of a mononucleotide repeat sequence. In the absence of MSH6 protein, the MSH2 protein will dimerize with the MSH3 protein forming the MutSβ complex, which has the ability to trigger repair of larger loop-out DNA mismatches, but also has some overlapping activity to repair lesions usually repaired by MutSα.
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.[296] The latter mechanism accounts for approximately 5% of all Lynch syndrome cases.[296] A deletion in one allele of exon 9 of the EPCAM (TACSTD1) gene, which is immediately upstream of the start site of MSH2 and in the same orientation, can lead to transcriptional read-through and methylation of the MSH2 promoter, and subsequent silencing of MSH2 in any tissue that expresses EPCAM. The presence of EPCAM pathogenic variants showing similar methylation-mediated MSH2 loss has been reported in numerous families.[297] On the strength of these observations, germline EPCAM testing is performed in patients with loss of MSH2 protein expression on IHC testing of their CRCs but who lack a detectable MSH2 germline pathogenic variant and is included with MSH2 testing in all colon cancer gene panels.
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.[288] A functional defect in MLH1 results in degradation of both MLH1 and PMS2, while a defect in PMS2 negatively affects only PMS2 expression. Thus, a loss of MLH1 and PMS2 indicates an alteration in MLH1 (promoter hypermethylation or germline variant), while loss of PMS2 expression indicates a germline PMS2 variant. However, among 88 individuals with PMS2-deficient CRC, PMS2 germline pathogenic variant testing followed by MLH1 germline pathogenic variant testing revealed pathogenic PMS2 variants in 49 individuals (74%) and MLH1 pathogenic variants in 8 individuals (12%).[298] Eighty-three percent of the alterations in MLH1 were missense variants, but two relatives carried identical MLH1 variants, and one individual, who developed two tumors with retained MLH1 expression, carried an intronic variant that led to skipping of exon 8.[298] Therefore, in CRCs with solitary loss of PMS2 expression, an MLH1 germline pathogenic variant should be sought if no PMS2 germline variant is found. Tumors with MSI and loss of MSH2 and MSH6 protein expression are generally indicative of an underlying MSH2 germline variant (inferred MSH2 pathogenic variant). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter.
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.[277,299] In a study that reported tumor testing results among MMR germline carriers enrolled through the Colon Cancer Family Registry, 7 of 24 carriers (28%) with MSH6 pathogenic variants had tumors that displayed normal protein expression on IHC staining. IHC tumor testing was more informative for MLH1 and MSH2 pathogenic variant carriers in which 93% of MLH1 carriers had correlating loss of MLH1 protein expression and 96% of MSH2 carriers had loss of MSH2 protein expression.[277]
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.)
Somatic MLH1 hypermethylation
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 [300] have a generalized excess of DNA methylation referred to as CIMP.[301] (Refer to the CIMP and the serrated polyposis pathway section in the Introduction section of this summary for more information.) Because loss of MLH1 protein expression on IHC occurs in both Lynch syndrome and sporadic tumors, its specificity for predicting germline MMR gene variants is lower than for the other MMR proteins, and additional molecular testing is often necessary to clarify the etiology of MLH1 absence.
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.[302-305] This suggests that detection of somatic BRAF V600E mutation detection in CRC may be useful in excluding individuals from germline variant testing. As a result, BRAF V600 testing and/or MLH1 hypermethylation assays are increasingly utilized in universal Lynch syndrome–testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caused by hypermethylation and germline MLH1 pathogenic variants. Making such a distinction is also a more cost-effective approach in excluding individuals from germline testing.
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. The incidence of consanguinity may be higher in rural and otherwise geographically and/or culturally isolated populations.[306]
Tumor studies yield characteristic abnormalities. In a series of 28 patients with BMMRD,[113] 17 brain tumors showed loss of staining for the MMR protein in the normal stromal cells in addition to neoplastic cells, showing a contradistinction from tumors in patients with Lynch syndrome in which normal staining is retained in nontumor cells. In contrast to this characteristic feature seen with IHC, PCR-based MSI analysis was not reliable, as 20 of 28 tumors were MSS. Of the tumors that were MSI-H, essentially all were colon cancers.
The PMS2 gene is markedly overrepresented in cases of BMMRD. It has been suggested that the presence of homozygosity of variants in the other MMR genes is a prenatally lethal state, while the otherwise milder expression of PMS2 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.)
Constitutional epimutation
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.[308] A constitutional epimutation (also referred to as a primary epimutation) is an acquired alteration in normal tissue that silences an active gene or activates an inactive gene.[309] Such epimutations occur most often in maternal alleles. In some cases all somatic cells appear involved, while in others there is evidence of mosaicism. Tumors in patients with primary epimutations are generally indistinguishable from those otherwise typical of Lynch syndrome germline variant carriers, including age at onset, tumor spectrum, and presence of abnormal MSI and IHC. Since these are not inherited in a Mendelian fashion, antecedent family history of tumors is minimal, and risk to offspring somewhat unpredictable. Epimutations present in a de novo case seem to typically be "erased" in the process of gametogenesis and to not be passed to the next generation. Very rare cases of inherited MLH1 epimutations have been reported.[310,311]
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 [312] or an inherited germline MLH1 methylation [313] add some complexity to the interpretation of MSI associated with absence of MLH1 expression. Akin to sporadic MSI, primary epimutation tumors show methylation of the MLH1 promotor and may show BRAF variants as well. As noted above, family history of cancer in such cases tends to be minimal or absent, as in true sporadic MSI. Distinguishing such cases from sporadic cases may call for assaying normal tissue (e.g., blood or normal colon mucosa) for evidence of MLH1 methylation, which will be absent from true sporadic cases and absent from carriers of conventional Lynch syndrome MMR pathogenic variants.
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.)
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