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5 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Lynch syndrome-associated bowel cancer is bowel cancer in someone born with a fault in one of the genes that proofread DNA copying errors. The tumours tend to arise younger and on the right side, they carry the mismatch repair defect that makes immunotherapy work, and the diagnosis changes the care of the whole family as well as the care of the patient.
What it is. Lynch syndrome is an inherited condition caused by a germline variant in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2, or by a deletion in EPCAM that silences MSH2. The proofreading system that corrects copying errors in repetitive DNA fails, the tumour accumulates insertions and deletions at those repeats, and the result is a mismatch repair-deficient, microsatellite-unstable cancer. The World Health Organization lists it among the genetic tumour syndromes of the digestive system, and it is the commonest inherited cause of bowel cancer (Nagtegaal 2020).
How it differs from its parent. Two things distinguish it from mismatch repair-deficient bowel cancer in general. The defect is inherited rather than acquired, so relatives are at risk and cascade testing follows the diagnosis; and the cancers behave differently by gene. In the Prospective Lynch Syndrome Database, 1,942 carriers without previous cancer were followed for 13,782 observation years under colonoscopic surveillance: cancers appeared from age 25 in MLH1 and MSH2 carriers but only from about 40 in MSH6 and PMS2 carriers, and the cumulative incidence of colorectal cancer by age 70 was 46 percent for MLH1, 35 percent for MSH2, 20 percent for MSH6 and 10 percent for PMS2. Endometrial cancer reached 34, 51, 49 and 24 percent by the same age. Colorectal cancer occurred despite surveillance but killed few people: ten-year crude survival was 91 percent when the first cancer was colorectal (Moller 2017). Sporadic mismatch repair-deficient cancers, by contrast, usually arise through methylation of the MLH1 promoter in older people through the serrated pathway, and have no implication for relatives.
| Setting | Approach | Guideline |
|---|---|---|
| Finding the syndrome | Mismatch repair immunohistochemistry or microsatellite instability testing on every colorectal cancer; MLH1 promoter methylation testing where MLH1 is lost, because most of those cancers are sporadic; germline testing when methylation is absent, then cascade testing of relatives. | not mapped |
| Risk reduction in carriers | Consider daily aspirin for more than two years (NICE NG151 1.1.1, from CAPP2); colonoscopic surveillance at intervals set by gene and age; discussion of the extent of colectomy when a cancer is found; gynaecological risk-reducing surgery after childbearing for women. | not mapped |