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.

Keywords: Lynch syndrome; Lynch‐like syndrome; colorectal cancer; methylation; stochastic epigenetic mutations.

FIGURE 1

(A) Scatter plots from principal component analysis (PCA) depicting the distribution of the sample cohorts across the first two principal components at the CpG site level. (B) Circos plot illustrating the genomic distribution of differentially methylated sites (red dots) across the human genome. These dots are positioned based on their –log10 (unadjusted p‐value). Notably, the X and Y‐chromosomes are excluded from the analysis.

FIGURE 2

SEMs distribution in LS, LLS and Sporadic groups. In each boxplot showing log10 transformed SEMs, the solid horizontal line within the box signifies the median of the dataset, and the box itself illustrates the interquartile range. By default, in the “ggplot” boxplot function, the whiskers stretch to data points that fall within 1.5 times the interquartile range (IQR) from the box. Individual data points beyond this range are depicted as dots, representing outliers.

FIGURE 3

(A) Venn diagrams illustrating the distribution of hypermethylated epivariations among the LS, LLS, and Sporadic groups, compared to healthy control (Refs) epivariations. (B) Venn diagrams illustrating the distribution of epivariations among the three cohorts and the prioritization of the 55 epivariations in common for LS phenotype.