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

[BACKGROUND] Lynch syndrome (LS), caused by pathogenic variants (PVs) in mismatch repair genes, increases the risk of several cancers. Surveillance guidelines vary internationally due to inconsistent risk estimates. This study refines cancer risk estimates by gene, sex, and age to support personalized recommendations.

[METHODS] This meta-analysis included studies reporting cumulative cancer risks in genetically confirmed LS PV carriers. PubMed was searched until December 31, 2024. Following the MOOSE (Meta-analyses Of Observational Studies in Epidemiology) guideline, data were extracted independently by 2 reviewers and analyzed using fixed (n = 2 estimates) or random-effects models (n > 2 estimates), stratified by gene, sex, cancer site, and study design: LS retrospective family (LSRF), LS prospective cohort (LSPC), and population-based case-control (PBCC) studies.

[RESULTS] Thirty-three studies were included, mostly LSRF. Meta-analysis of LSRF showed that colorectal cancer risk at 40 years was markedly lower in MSH6 and PMS2 carriers (<2%) than in MLH1 and MSH2 (>4%). For endometrial cancer, risks at 50 years were 8.3% (95% CI = 5.1 to 13.4), 8.7% (95% CI = 3.8 to 18.7), 5.2% (95% CI = 2.3 to 11.2), and 3.0% (95% CI = 1.0 to 8.0) for MLH1, MSH2, MSH6, and PMS2, respectively. For ovarian cancer, risks at 40 years were 1.2% (95% CI = 0.6 to 2.7) and 0.9% (95% CI = 0.5 to 1.8) for MLH1 and MSH2, respectively. Few studies addressed other cancer types, highlighting the need for additional data.

[CONCLUSIONS] This is the first meta-analysis providing stratified cancer risk estimates by cancer site, gene, and study design. These findings support gene-specific surveillance strategies, such as initiating colonoscopy at 30-35 years for MSH6 and PMS2 carriers, postponing hysterectomy after 50 years for PMS2 carriers, and delaying oophorectomy after 45 years for MLH1 and MSH2 PV carriers.