Clinical and genomic features of Lynch syndrome differ by tumor site and disease spectrum

Lynch Syndrome (LS) carriers occasionally develop central nervous system (CNS) malignancies or tumors in organs not traditionally linked to the syndrome. These tumors are poorly characterized in the literature, and there is no sufficient consensus on guidelines and management recommendations for these tumors. Here we study LS from the tumor perspective and profile 238 pan-cancer specimens from 228 genetically confirmed LS carriers. Tumors are stratified into CNS LS-related, non-CNS LS-related, and non-CNS LS-unrelated groups according to anatomic site and established LS tumor spectrum. Comparative analyses against TCGA reveal significant alterations in LS incidence within endometrial and hepatic cancers. Across the three groups, we reveal marked heterogeneity in germline pathogenic-variant distribution, age at diagnosis, somatic mutation landscapes, tumor mutational burden, and microsatellite-instability status. This site- and spectrum-based stratification of a large, pan-cancer LS cohort underscores the heterogeneity of the LS and provides a data-driven foundation for refining future disease management strategies.