Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Fifty-eight probands harboring MSH2-deficient tumors were included. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS).
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