Residency · Residency · Gastroenterology

Hereditary Colorectal Cancer Syndromes

Overview

Approximately 5 to 10% of all colorectal cancer is attributable to identifiable germline mutations, and this proportion rises to 20 to 25% among cases of early-onset colorectal cancer diagnosed before age 50. Universal tumor testing with mismatch repair immunohistochemistry and/or microsatellite instability analysis is now recommended by the NCCN for all newly diagnosed colorectal cancers, regardless of age or family history. Multi-gene panel testing has increasingly replaced sequential single-gene testing, offering higher diagnostic yield by simultaneously evaluating multiple cancer predisposition genes.

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer, HNPCC)

Genetics

Lynch syndrome is the most common hereditary colorectal cancer syndrome, accounting for 3 to 5% of all colorectal cancer, and is inherited in an autosomal dominant pattern. It results from germline mutations in the DNA mismatch repair genes. MLH1, located on chromosome 3p21, is the most commonly affected gene, accounting for approximately 40% of Lynch cases. MSH2, on chromosome 2p16, accounts for 34%. MSH6, also on chromosome 2p16, accounts for 18% and is associated with an attenuated phenotype characterized by later onset and a greater predilection for endometrial cancer relative to colorectal cancer. PMS2, on chromosome 7p22, accounts for 8% and demonstrates an attenuated phenotype with lower penetrance. EPCAM deletion, found in 1 to 3% of Lynch syndrome cases, is located upstream of MSH2 and leads to epigenetic silencing of MSH2 expression.

Loss of mismatch repair function results in microsatellite instability (MSI-high), which drives an accelerated adenoma-to-carcinoma progression sequence that takes only 1 to 3 years compared with 10 to 15 years in sporadic colorectal cancer.

Cancer Risks (Lifetime)

The lifetime risk of colorectal cancer in Lynch syndrome ranges from 40 to 80%, with the highest risk conferred by MLH1 and MSH2 mutations and a substantially lower risk of 10 to 20% with PMS2 mutations. Endometrial cancer risk is 25 to 60%, highest with MSH2 and MSH6 mutations. Ovarian cancer risk is 4 to 24%, and gastric cancer risk is 1 to 13%, with higher rates observed in Asian populations. Urinary tract cancer involving the renal pelvis and ureter carries a risk of 1 to 12%. Additional associated malignancies include small bowel, hepatobiliary, and pancreatic cancers, as well as brain tumors in the Turcot variant (characteristically glioblastoma) and sebaceous neoplasms in the Muir-Torre variant.

Diagnosis

Universal Tumor Testing

Mismatch repair immunohistochemistry tests for protein expression of MLH1, MSH2, MSH6, and PMS2, with loss of staining indicating deficient mismatch repair. MSI testing is PCR-based using the Bethesda panel (BAT-25, BAT-26, D2S123, D5S346, D17S250), with MSI-high defined as instability in 2 or more of 5 markers. When MLH1 loss is identified, reflex testing for BRAF V600E mutation and/or MLH1 promoter methylation is essential: if BRAF V600E is positive or MLH1 methylation is present, the finding indicates sporadic MSI-high colorectal cancer rather than Lynch syndrome. If BRAF V600E is negative and no methylation is detected, germline MLH1 testing should be pursued. Loss of MSH2 and/or MSH6 on immunohistochemistry should prompt germline testing for MSH2, MSH6, and EPCAM.

Amsterdam II Criteria (Clinical — Limited Sensitivity)

The Amsterdam II criteria require 3 or more relatives with Lynch-associated cancer (one of whom must be a first-degree relative of the other two), 2 or more successive generations affected, and at least one case diagnosed before age 50, with familial adenomatous polyposis excluded. These clinical criteria have only 40 to 80% sensitivity for Lynch syndrome and hold primarily historical significance.

Revised Bethesda Guidelines

The Revised Bethesda Guidelines identify patients who should undergo tumor MSI testing. Criteria include colorectal cancer diagnosed before age 50, synchronous or metachronous colorectal cancer or other Lynch-associated cancer, MSI-high histologic features (tumor-infiltrating lymphocytes, Crohn-like lymphoid reaction, mucinous or signet ring differentiation, or medullary histology) in a patient under 60 years, colorectal cancer in a patient with at least one first-degree relative with a Lynch-associated cancer where one individual was diagnosed before age 50, and colorectal cancer in a patient with 2 or more first- or second-degree relatives with Lynch-associated cancer.

Surveillance Recommendations

Colonoscopy should begin at age 20 to 25, or 2 to 5 years before the youngest diagnosis in the family if earlier, with repeat examinations every 1 to 2 years. For MSH6 and PMS2 carriers, surveillance may begin at age 25 to 30 given their later disease onset. Endometrial cancer screening with annual endometrial sampling should start at age 30 to 35, or risk-reducing hysterectomy with bilateral salpingo-oophorectomy may be considered after childbearing is complete. Upper endoscopy should be considered starting at age 30 to 35 and repeated every 3 to 5 years to assess gastric and duodenal cancer risk, with Helicobacter pylori testing and eradication. Annual urinalysis for urinary tract cancer screening should begin at age 30 to 35.

Aspirin chemoprevention has demonstrated significant benefit in Lynch syndrome, with the CAPP2 trial showing a 63% reduction in colorectal cancer risk with 600 mg per day. The CAPP3 trial is currently evaluating lower doses of 100 mg and 300 mg to optimize the risk-benefit profile.

<image>A diagnostic algorithm for universal tumor testing in colorectal cancer to identify Lynch syndrome. Start with "All newly diagnosed CRC." First step: "Perform MMR IHC (MLH1, MSH2, MSH6, PMS2) AND/OR MSI testing on tumor." Branch 1: "MMR proficient / MSS" -> "Lynch unlikely (consider other hereditary syndromes if strong family history)." Branch 2: "Loss of MSH2 and/or MSH6" -> "Germline testing for MSH2, MSH6, EPCAM." Branch 3: "Loss of MLH1 +/- PMS2" -> "Test for BRAF V600E and/or MLH1 promoter methylation." If BRAF V600E positive OR methylation present: "Sporadic MSI-high CRC (NOT Lynch)." If BRAF negative AND no methylation: "Germline testing for MLH1." Branch 4: "Isolated loss of PMS2" -> "Germline testing for PMS2." Include a box listing Lynch-associated cancers with lifetime risk percentages: CRC 40-80%, endometrial 25-60%, ovarian 4-24%, gastric 1-13%, urinary tract 1-12%. Use color coding: green for Lynch excluded, red for Lynch confirmed, yellow for further testing needed. Include a note: "Universal testing recommended by NCCN for ALL CRC regardless of age or family history."</image>

Familial Adenomatous Polyposis (FAP)

Classic FAP

Classic familial adenomatous polyposis results from germline mutations in the APC gene on chromosome 5q21 and is inherited in an autosomal dominant pattern with nearly 100% penetrance. Affected individuals develop more than 100 adenomatous polyps, often numbering in the hundreds to thousands, with onset typically in adolescence. Without surgical intervention, the mean age of colorectal cancer development is 39 years, and the risk of colorectal cancer approaches 100% by age 40 to 50. Approximately 25 to 30% of cases arise from de novo mutations without a family history. Genotype-phenotype correlations are well established: mutations at codon 1309 are associated with severe polyposis and early colorectal cancer, codon 1061 mutations produce a moderate phenotype, and mutations at the extreme 5-prime or 3-prime ends of the gene or in exon 9 are associated with attenuated disease.

Attenuated FAP (AFAP)

Attenuated FAP results from APC mutations at the extreme 5-prime end (exons 1 through 4), the extreme 3-prime end (after codon 1580), or exon 9. The phenotype is characterized by 10 to 99 adenomas with a later age of onset (mean 55 years) and a right-sided colonic predominance. The lifetime colorectal cancer risk is approximately 70% by age 80.

Extracolonic Manifestations of FAP

Duodenal and ampullary adenomas develop in 50 to 90% of FAP patients and are staged according to the Spigelman classification (stages I through IV), with a duodenal cancer risk of 4 to 12%. Desmoid tumors occur in 10 to 30%, are often mesenteric in location, and demonstrate APC genotype dependence with 3-prime mutations conferring higher risk. Desmoid tumors represent a major cause of morbidity and mortality after colectomy, and treatment options include observation, sulindac, tamoxifen, chemotherapy with doxorubicin and dacarbazine, and surgery, although surgical recurrence rates are high.

Fundic gland polyps are found in 50 to 90% of FAP patients and demonstrate dysplasia in 25 to 40%, in contrast to sporadic fundic gland polyps, though the overall cancer risk remains low. Thyroid cancer, predominantly the papillary cribriform-morular variant, occurs in 2 to 12% with a female predominance. Hepatoblastoma may develop in childhood (before age 5), warranting screening with alpha-fetoprotein and liver ultrasound every 3 to 6 months. Congenital hypertrophy of the retinal pigment epithelium, when bilateral, is pathognomonic for FAP and is a benign finding. Osteomas and dental abnormalities including supernumerary teeth constitute the Gardner syndrome phenotype.

Management

Screening for FAP should begin with annual flexible sigmoidoscopy or colonoscopy starting at age 10 to 12, with consideration of full colonoscopy by age 15. Surgical options include total proctocolectomy with ileal pouch-anal anastomosis (J-pouch), which is the definitive procedure as it removes all at-risk mucosa except the pouch and is typically recommended by the late teens to early twenties. Total abdominal colectomy with ileorectal anastomosis preserves the rectum with lower surgical morbidity but requires ongoing rectal surveillance every 6 to 12 months, as the risk of rectal cancer in the retained rectum reaches 12 to 30% at 25 years. Surgical timing should be individualized based on polyp burden, genotype, and patient preference.

Chemoprevention with sulindac reduces polyp number and size but does not prevent colorectal cancer. Celecoxib is FDA-approved for FAP polyp reduction, but cardiovascular risk limits its long-term use. Neither agent is a substitute for surgical management. Upper gastrointestinal surveillance with esophagogastroduodenoscopy and side-viewing duodenoscopy should begin at age 20 to 25 or at diagnosis, with the surveillance interval guided by Spigelman stage: every 3 to 5 years for stages I to II, every 1 to 2 years for stage III, and consideration of surgery for stage IV.

MUTYH-Associated Polyposis (MAP)

MUTYH-associated polyposis results from mutations in the MUTYH gene on chromosome 1p34, which encodes a component of the base excision repair pathway. It is uniquely inherited in an autosomal recessive pattern, requiring biallelic mutations for the full phenotype, although heterozygous carriers have a mildly increased colorectal cancer risk. The most common mutations in European populations are Y179C and G396D. The phenotype consists of 20 to more than 100 adenomas, resembling attenuated FAP, with an increase in serrated lesions as well. The lifetime colorectal cancer risk for biallelic carriers is approximately 80% by age 70, and duodenal adenomas develop in 20 to 30%. Management follows a similar approach to attenuated FAP, with colonoscopy every 1 to 2 years starting at age 25 to 30 and surgical discussion when polyps become unmanageable endoscopically.

Hamartomatous Polyposis Syndromes

Peutz-Jeghers Syndrome (PJS)

Peutz-Jeghers syndrome is caused by germline mutations in the STK11/LKB1 gene on chromosome 19p13 and is inherited in an autosomal dominant fashion. It is characterized by mucocutaneous melanin pigmentation of the lips, buccal mucosa, and digits, along with hamartomatous polyps that display a distinctive arborizing smooth muscle pattern. Polyps are distributed throughout the gastrointestinal tract, with the small bowel more commonly affected than the colon and stomach.

The lifetime cancer risks are substantial and diverse: colorectal cancer 39%, small bowel cancer 13%, gastric cancer 29%, pancreatic cancer 11 to 36%, breast cancer 32 to 54%, ovarian cancer 21% (specifically sex cord tumor with annular tubules, or SCTAT), and cervical adenoma malignum. Surveillance includes colonoscopy and upper endoscopy starting at age 8 to 10 if symptoms are present or at age 18 if asymptomatic, small bowel imaging with MR enterography or video capsule endoscopy starting at age 8 to 10, pancreatic surveillance with EUS or MRI/MRCP at age 30 to 35, and mammography starting at age 25. A major acute complication is intussusception from small bowel polyps, which may present as a surgical emergency in children and adolescents.

Juvenile Polyposis Syndrome (JPS)

Juvenile polyposis syndrome results from mutations in SMAD4 (20% of cases) or BMPR1A (20%) and is inherited in an autosomal dominant pattern. Diagnostic criteria include 5 or more juvenile polyps in the colon, juvenile polyps throughout the gastrointestinal tract, or any juvenile polyp in conjunction with a positive family history. The lifetime colorectal cancer risk ranges from 17 to 68%, and gastric cancer risk is particularly elevated with SMAD4 mutations. An important association with SMAD4 mutations is hereditary hemorrhagic telangiectasia (HHT, also known as Osler-Weber-Rendu syndrome), which necessitates screening for pulmonary arteriovenous malformations. Surveillance consists of colonoscopy and upper endoscopy starting at age 12 to 15, repeated every 1 to 3 years.

Cowden Syndrome (PTEN Hamartoma Tumor Syndrome)

Cowden syndrome results from mutations in the PTEN gene on chromosome 10q23 and follows autosomal dominant inheritance. Gastrointestinal polyps are of mixed histology, including hamartomatous, ganglioneuromatous, inflammatory, and adenomatous types. Pathognomonic dermatologic features include trichilemmomas, oral papillomas, and acral keratoses. The cancer risks are extensive: breast cancer 85%, thyroid cancer 35%, endometrial cancer 28%, colorectal cancer 9 to 16%, and renal cancer 34%. Surveillance recommendations include colonoscopy starting at age 35 to 40 every 5 years, annual thyroid ultrasound from the time of diagnosis, mammography and breast MRI starting at age 30, and annual dermatologic examination.

<image>A comparison table of hereditary colorectal cancer syndromes displayed as an infographic. Create five columns for: Lynch, FAP, MAP, PJS, and JPS. Rows for: Gene/Inheritance (with chromosome location), Polyp Number, Polyp Type, Polyp Distribution, CRC Lifetime Risk (as a horizontal bar graph within each cell), Key Extracolonic Cancers (icons or abbreviated text), Pathognomonic Features (distinctive clinical/endoscopic finding for each), and Surveillance Start Age. Lynch: MLH1/MSH2/MSH6/PMS2 (AD), few adenomas, conventional adenomas, throughout colon, 40-80%, endometrial/ovarian/gastric/urinary, MSI-high tumor. FAP: APC (AD), >100 to thousands, conventional adenomas, throughout colon (carpet of polyps), ~100%, duodenal/desmoid/thyroid, CHRPE. MAP: MUTYH (AR), 20-100+, adenomas + serrated, throughout colon, 80%, duodenal, biallelic required. PJS: STK11 (AD), 10s to 100s, hamartomatous (arborizing SM), small bowel predominant, 39%, breast/pancreas/ovarian/cervical, lip melanin pigmentation. JPS: SMAD4/BMPR1A (AD), 5-200, juvenile (cystic, inflamed), colon predominant, 17-68%, gastric (SMAD4)/HHT, SMAD4+HHT association. Use distinct colors for each syndrome column. Include small representative polyp histology sketches for each type.</image>

Serrated Polyposis Syndrome (SPS)

Diagnostic Criteria (WHO 2019)

Serrated polyposis syndrome is defined by meeting either of two criteria. Criterion 1 requires 5 or more serrated lesions or polyps proximal to the rectum, all measuring 5 mm or larger, with at least 2 measuring 10 mm or larger. Criterion 2 requires more than 20 serrated lesions or polyps of any size distributed throughout the colon, with at least 5 proximal to the rectum. Only one criterion needs to be fulfilled for the diagnosis.

Clinical Features

Serrated polyposis syndrome is the most common polyposis syndrome encountered in clinical practice. The colorectal cancer risk is 15 to 30%, and the syndrome is often first diagnosed at the time of colorectal cancer presentation. Although it may be associated with germline RNF43 mutations in rare cases, the genetic basis is mostly polygenic and multifactorial. First-degree family members of affected individuals carry a 2- to 5-fold increased colorectal cancer risk.

Management

The primary management strategy is to clear all polyps endoscopically when feasible, with colonoscopy repeated every 1 to 2 years. Surgery should be considered if polyps become unmanageable endoscopically or if colorectal cancer is diagnosed. First-degree relatives should undergo colonoscopy starting at age 40 or 10 years before the proband's age at diagnosis, whichever is earlier, with repeat screening every 5 years.

Genetic Counseling and Testing

Indications for Referral

Referral for genetic counseling should be considered for patients with colorectal cancer diagnosed before age 50, tumors demonstrating deficient mismatch repair or MSI-high status (after ruling out sporadic causes), multiple primary colorectal cancers or Lynch-associated cancers, a cumulative lifetime total of 10 or more adenomas, hamartomatous polyps, or a strong family history meeting Amsterdam criteria.

Multi-Gene Panel Testing

Multi-gene panel testing has become the standard approach, with panels testing 15 to more than 80 genes simultaneously. This methodology provides higher diagnostic yield than sequential testing and may identify mutations in unexpected genes. Variants of uncertain significance are reported in 10 to 40% of results and should not change clinical management, though reclassification over time may clarify their significance. Incidental findings may identify cancer predisposition genes unrelated to colorectal cancer.

Key Clinical Pearls

• Universal tumor testing (MMR IHC +/- MSI) is recommended for ALL newly diagnosed CRC — not just young patients
• MLH1 loss on IHC requires BRAF V600E and/or MLH1 methylation testing to distinguish sporadic from Lynch
• MUTYH-associated polyposis is autosomal RECESSIVE — both alleles must be mutated; heterozygous carriers have only mildly increased risk
• Aspirin chemoprevention in Lynch syndrome: CAPP2 trial showed 63% CRC risk reduction with 600 mg/day; optimal dose under study (CAPP3)
• FAP patients require upper GI surveillance (duodenal cancer is the leading cause of death after colectomy)
• SMAD4-associated JPS overlaps with HHT — screen for pulmonary AVMs
• Serrated polyposis syndrome is the most common polyposis syndrome encountered in practice and carries significant CRC risk
• All patients with early-onset CRC (<50) should be referred for genetic counseling and multi-gene panel testing

References

1. Gupta S, et al. NCCN Clinical Practice Guidelines: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2023.
2. Syngal S, et al. ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes. Am J Gastroenterol. 2015;110(2):223-262.
3. Burn J, et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome) — 10-year follow-up of the CAPP2 randomised trial. Lancet. 2020;395(10240):1855-1863.
4. Vasen HFA, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. 2008;57(5):704-713.
5. IJspeert JEG, et al. Serrated neoplasia — role in colorectal carcinogenesis and clinical implications. Nat Rev Gastroenterol Hepatol. 2015;12(7):401-409.

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