Hereditary Colorectal Cancer — FAP vs Lynch Syndrome: Genes, Criteria, Screening and Surgery

Inherited mutations cause roughly 5% to 10% of colorectal cancers, and the commonest hereditary form is Lynch syndrome. Familial adenomatous polyposis (FAP) is the second most common inherited polyposis syndrome and accounts for about 1% of colorectal cancer (StatPearls). They are the two syndromes exam-setters contrast most often: one is a polyposis syndrome, the other is non-polyposis.

FAP results from a germline mutation of the APC gene, a tumour suppressor on chromosome 5, inherited in an autosomal dominant manner. Untreated patients develop hundreds to thousands of polyps throughout the colon and rectum, often in the early teens, with an almost 100% lifetime risk of colorectal cancer, typically by about age 40. Roughly 20% to 30% of patients have no family history because of de novo mutations, and 10% to 30% have no detectable APC mutation, yet relatives are still screened as for a proven mutation.

More than 100 adenomatous polyps should make you strongly consider FAP, and a finding of 10 or more colonic polyps at one colonoscopy is highly suggestive, especially in younger patients. Genetic testing is recommended when colonoscopy shows over 20 adenomatous polyps or when FAP-associated cancers are found.

• Congenital hypertrophy of the retinal pigment epithelium (CHRPE): flat pigmented retinal lesions, specific to FAP, usually asymptomatic.
• Gardner features: osteomas of the mandible or skull and dental abnormalities such as impacted teeth.
• Upper GI: gastric and duodenal polyps with risk of gastric and duodenal cancer.
• Other tumours: desmoid fibromatosis, hepatoblastoma and thyroid cancer.

In APC mutation carriers the National Comprehensive Cancer Network advice quoted in StatPearls is annual sigmoidoscopy or colonoscopy from age 10 to 15, with upper endoscopy at 20 to 25 years (earlier if colectomy happens before that) to examine the stomach and duodenum.

Colectomy is the primary intervention that substantially lowers cancer risk. Total proctocolectomy with ileal pouch-anal anastomosis (or end ileostomy) gives the highest likelihood of eliminating at-risk mucosa. Total abdominal colectomy with ileorectal anastomosis is less extensive and preserves the rectum, improving continence and sexual function, but the retained rectum can still develop adenocarcinoma, so regular endoscopic surveillance (every 3 to 6 months in the chapter) is needed.

Drug options have limited success. Sulindac, an NSAID, reduced adenoma number by nearly 50% and size by 65% in small studies, but adenomas recurred when it was stopped; it is an option for patients with a retained rectum. See NSAIDs.

Lynch syndrome arises from a germline mutation in one of four mismatch repair (MMR) genes — *MLH1, MSH2, MSH6, PMS2* — and large deletions in *EPCAM* can also cause it by silencing MSH2. MMR genes correct wrongly paired bases during DNA replication, so their failure leaves microsatellite instability (MSI). It is autosomal dominant, and first-degree relatives have a 50% chance of carrying the variant.

Lifetime risk of colorectal cancer is about 80% and of endometrial cancer up to 60%; endometrial cancer is the commonest malignancy after colorectal cancer. Other associated cancers include gastric, ovarian, small bowel, urothelial, prostate, biliary, pancreatic, adrenocortical and brain cancers, plus sebaceous gland adenomas and keratoacanthomas (Muir-Torre syndrome). Tumours tend to occur in the right colon, in younger patients, with synchronous or metachronous lesions, and they progress faster from adenoma to carcinoma.

The Amsterdam II criteria need several relatives with a Lynch-related cancer (colorectal, endometrial, small bowel, ureter or renal pelvis) plus: at least 2 successive generations affected; one is a first-degree relative of the other two; at least 1 diagnosed before age 50; no evidence of FAP; and pathological verification. Remember it as the 3-2-1 rule: three relatives, two generations, one under 50. The revised Bethesda guidelines select tumours for MSI testing instead of families.

These criteria are imperfect: about 50% of carriers are missed, and about 50% of patients who meet them do not have Lynch syndrome. Persons who qualify undergo immunohistochemistry and/or MSI analysis, then germline testing. Absent staining for at least one MMR protein means mismatch repair deficiency. If MLH1 (alone or with PMS2) is lost, test for BRAF V600E or MLH1 promoter methylation: methylation points to a sporadic cancer rather than Lynch syndrome. Both PCR and IHC have a false-negative rate of about 5% to 10%.

Aspirin may lower colon cancer risk in Lynch syndrome, but the optimal dose and duration remain uncertain; doses of 325 to 650 mg daily have been suggested, and 81 mg may help. MSI-high tumours trigger a heavy lymphocytic reaction, so immune checkpoint antibodies such as pembrolizumab are used against them. Family members should be told so that at-risk relatives can be tested. See NSAIDs for aspirin pharmacology.