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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.
How common it is. Modelling of 5,744 families put the population prevalence of a mismatch repair variant at 1 in 279 (Win 2017); Cancer Research UK records that hereditary non-polyposis colorectal cancer accounts for 1 to 4 percent of colon cancers, and that around 9 in 10 men and 7 in 10 women with it develop bowel cancer by age 70.
How it is treated. The cancer itself is treated as colorectal cancer of the same stage and molecular profile, which in practice means the mismatch repair-deficient pathways: checkpoint inhibitors in metastatic disease, and the neoadjuvant and adjuvant immunotherapy strategies the parent record carries. What is specific to Lynch syndrome is everything around the tumour. NICE NG151 (1.1.1) says to consider daily aspirin for more than two years to reduce colorectal cancer risk, on the strength of CAPP2, in which 600 mg daily cut colorectal cancer over ten years (hazard ratio 0.65 by intention to treat, 0.56 in those who completed two years) (Burn 2020). Colonoscopic surveillance, the extent of surgery when a cancer is found, gynaecological risk-reducing surgery and cascade testing of relatives follow the British Society of Gastroenterology, ACPGBI and UK Cancer Genetics Group guidelines (Monahan 2020).
About 1 in 279 people carry a mismatch repair variant (MLH1 1 in 1,946, MSH2 1 in 2,841, MSH6 1 in 758, PMS2 1 in 714), and hereditary non-polyposis colorectal cancer accounts for 1 to 4 percent of colon cancers (Win 2017; Cancer Research UK).
Right-sided tumours behave differently from left-sided and rectal ones; the colon drains along its mesenteric vessels, the rectum into the mesorectum and pelvic side wall.
Same organ: Colon cancer (adenocarcinoma of the colon), Micropapillary adenocarcinoma of the colon and rectum, Adenoma-like adenocarcinoma of the colon and rectum, Familial adenomatous polyposis-associated colorectal cancer, Mucinous adenocarcinoma of the colon and rectum, Signet ring cell carcinoma of the colon and rectum, Medullary carcinoma of the colon, Serrated adenocarcinoma of the colon and rectum, Peritoneal mesothelioma, Colorectal cancer, Rectal cancer, Mismatch-repair deficient (MSI-high) colorectal cancer, BRAF V600E-mutant colorectal cancer, HER2-amplified colorectal cancer, KRAS G12C-mutant colorectal cancer, Early-onset colorectal cancer (under 50), Anal cancer (squamous cell carcinoma), Appendiceal cancer and pseudomyxoma peritonei, Small intestine cancer (small bowel adenocarcinoma), Small intestinal neuroendocrine tumours, Anal high-grade squamous intraepithelial lesions (precursor), Localised anal squamous cell carcinoma (stage I to III), Metastatic and recurrent anal squamous cell carcinoma, Low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei, Appendiceal adenocarcinoma (mucinous and non-mucinous, including signet ring cell), Goblet cell adenocarcinoma of the appendix, Localised small bowel adenocarcinoma (stage I to III, resected), Advanced and metastatic small bowel adenocarcinoma
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.
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.
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Query for this cancer: (TITLE:"Lynch syndrome-associated colorectal cancer" OR ABSTRACT:"Lynch syndrome-associated colorectal cancer" OR TITLE:"Lynch syndrome-associated colorectal cancer inherited mismatch repair variant; about 1 to 4 percent of colon cancers" OR ABSTRACT:"Lynch syndrome-associated colorectal cancer inherited mismatch repair variant; about 1 to 4 percent of colon cancers" OR TITLE:"Lynch syndrome hereditary dMMR, ~3%" OR ABSTRACT:"Lynch syndrome hereditary dMMR, ~3%" OR TITLE:"Hereditary non-polyposis colorectal cancer" OR ABSTRACT:"Hereditary non-polyposis colorectal cancer" OR TITLE:"HNPCC" OR ABSTRACT:"HNPCC" OR TITLE:"Lynch syndrome bowel cancer" OR ABSTRACT:"Lynch syndrome bowel cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Lynch syndrome-associated colorectal cancer, not a curated reading list.
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