Risks of extracolonic tumours in patients with Lynch syndrome: a nationwide multicentre cohort study in Japan

Lynch syndrome (LS) is a genetic condition characterized by an increased risk of colorectal cancer and other associated malignancies. With the limited information available regarding extracolonic tumours, this study aimed to explore tumours associated with LS in the Japanese population and discuss the potential differences in causative pathogenic genetic variants and their phenotypic expression compared with Western cohorts.

This multicentre retrospective cohort study analysed 316 genetically confirmed LS cases (148 men and 168 women) from 13 institutions. We analysed the incidence of extracolonic LS-associated tumours according to sex and gene variants, including MLH1 (124 cases), MSH2 (139), MSH6 (37), PMS2 (11), and EPCAM (5). Extracolonic tumour types assessed included 88 endometrial, 47 gastric, 27 small intestinal, 21 urothelial, 13 ovarian, 8 biliary tract, 5 brain, three pancreatic, and 18 other cancers.

The cumulative risk by age 70 was 66% for endometrial cancer, 23% for gastric cancer, 14% for small intestine cancer, 10% for upper urothelial cancer, 9% for ovarian cancer, and 3% for biliary tract cancer. The mean age at diagnosis varied, with gastric and small intestinal cancers presenting later in life than urothelial, endometrial, and ovarian cancers. Men had a higher risk of most cancers, except for gynaecological cancers. Gastric and urothelial cancers were primarily associated with MLH1 and MSH2 pathogenic variants.

This study highlights the need for tailored surveillance programmes based on cancer type, sex, causative pathogenic genetic variants, and risk profiles to effectively manage LS in Japan.