Germline Mismatch Repair Variant Detection and Surveillance Outcomes in Patients with Lynch Syndrome: A Review

Abstract

Lynch syndrome is the commonest inherited cause of colorectal cancer, and carriers are enrolled in colonoscopic surveillance on the assumption that removing adenomas prevents cancer. Prospective data show cancers continuing to occur at high rates despite that surveillance, and no advantage from shortening the interval. Objectives: To review the published evidence on germline mismatch repair variant detection and surveillance outcomes in Lynch syndrome: how carriers are identified, what cancer risk each gene confers, what colonoscopic surveillance achieves, and why shorter intervals have not delivered what was expected. Material and Methods: Narrative review of prospective cohort reports, registry analyses, comparative surveillance studies and society guidelines indexed
in PubMed and the major gastroenterology and genetics journals. Studies were eligible if they reported gene-specific cancer risk in variant carriers, the yield or performance of detection strategies, or outcomes of colonoscopic surveillance. No new patient data were generated; every estimate quoted is one published by the original investigators. Results: Among 8,500 carriers under colonoscopic surveillance, cumulative colon cancer risk by age 65 was 48.4, 41.5, 12.7 and 9.5 per cent in men and 36.3, 29.8, 10.1 and 2.8 per cent in women for path_MLH1, path_MSH2, path_MSH6 and path_PMS2 respectively. Rectal cancer followed a different ordering, highest in path_MSH2 at 12.6 per cent in men. In 6,350 carriers, no significantly increased cancer risk was demonstrated for path_PMS2, and
path_MSH6 behaved as a sex-limited trait with high endometrial but only modestly raised colorectal risk. Among 218 cancers diagnosed during surveillance, the proportion presenting at stage III or IV did not differ by time since the previous colonoscopy, at 16.7, 19.4, 9.9 and 15.1 per cent across intervals of under 1.5, 1.5 to 2.5, 2.5 to 3.5 and over 3.5 years (p = 0.34). Conclusion: Gene-specific risk differs enough that a single surveillance protocol for all carriers is not defensible, and current guidelines have moved
accordingly. The absence of any stage or incidence benefit from shorter intervals suggests that colorectal cancer in this syndrome does not always arise through a slow adenoma sequence, which is the premise surveillance was built on. Abbreviations: LS – Lynch Syndrome, MMR – Mismatch Repair, path_MMR – Pathogenic Mismatch Repair Variant, CRC – Colorectal Cancer, MSI – Microsatellite Instability, dMMR – Deficient Mismatch Repair, IHC – Immunohistochemistry, EPCAM – Epithelial Cell Adhesion Molecule, PLSD –
Prospective Lynch Syndrome Database, EHTG – European Hereditary Tumour Group, ESCP – European Society of Coloproctology, AJCC – American Joint Committee on Cancer.