Cancer risks in Lynch syndrome carriers: systematic review and meta-analysis

Lynch syndrome (LS) is caused by pathogenic variants (PVs) in mismatch repair (MMR) genes, and increases the risk of several types of cancer. A systematic review and meta-analysis of studies published up to the end of 2024 investigated cancer risk estimates in LS patients by gene, sex, and age. The analysis included 33 studies, most LS retrospective family studies. Meta-analysis showed that colorectal cancer risk by age 40 years was markedly lower in MSH6 and PMS2 carriers (< 2%) than in MLH1 and MSH2 carriers (≥ 4%). For endometrial cancer, risks at 50 years of age were 8.3% for MLH1, 8.7% for MSH2, 5.2% for MSH6, and 3.0% for PMS2. For ovarian cancer, risks at 40 years of age were 1.2% for MLH1 and 0.9% for MSH2. Few studies addressed other cancer types. The authors conclude that these findings support gene-specific surveillance strategies, such as initiating colonoscopy at age 30-35 years for MSH6 and PMS2 carriers, postponing hysterectomy after age 50 years for PMS2 carriers, and delaying oophorectomy after age 45 years for MLH1 and MSH2 PV carriers.