Comprehensive genetic and epigenetic characterization of Lynch-like syndrome patients.

Abstract

Lynch-like syndrome (LLS) presents very similar clinicopathological characteristics to Lynch syndrome (LS) but the mechanism for cancer predisposition remains unknown. The present study aims to investigate the causal mechanism of LLS by a comprehensive genetic and epigenetic approach. Thirty-two LLS and 34 LS patients with colorectal cancer (CRC) fitting the Amsterdam and Bethesda criteria were included, along with 29 CRC sporadic patients, and analyzed for the presence of pathogenic variants in 94 genes associated with hereditary tumors. The cohorts were also characterized for the methylation profile and examined through a sample group analysis and a Stochastic Epigenetic Mutations (SEMs) analysis in comparison with 29 age-matched healthy controls. The multigene panel analysis revealed the presence of pathogenic variants in non-mismatch repair (MMR) genes and three variants classified as pathogenic/likely pathogenic possibly predisposing to LLS. The epigenetic analysis showed epivariations targeting genes associated with LS or DNA repair, most of them associated with the Fanconi Anemia pathway, which could explain the susceptibility to cancer. Our results highlight the need for using extended genetic and epigenetic analyses to understand the causal mechanism of LLS.