Implication of DNA repair genes in Lynch-like syndrome

Many colorectal cancers (CRCs) that exhibit microsatellite instability(MSI) are not explained by MLH1promoter methylation or germline mutationsin mismatch repair (MMR) genes, which cause Lynch syndrome(LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutationsin MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germlinesequence analysis in LLS patients and determined their tumor’s mutationalprofiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1methylation. Suspected LS cases were exome sequenced to identify germlineand somatic mutations. Single nucleotide variants were used to characterize mutationalsignatures. We identified 23 suspected LS cases. Germlinesequence analysis of 16 available samples identified five cases with LS mutationsand 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutationand lossof heterozygosity. LLS patients were relatively young and had excess first-degree relativeswith cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutationalsignature compared to tumors from LLS patients lacking germline mutationsin these genes. In summary, more than a third of the LLS patients studied had germline mutationsin genes that maintain genome integrity and their tumors had a distinct mutationalsignature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.