Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome

SIMPLE SUMMARY: A significant proportion of families with a clinical suggestion of Lynch syndrome and screened for the known MMR genes remain without a molecular diagnosis. These patients, who generally show a suggestive family pedigree or early-onset tumors with MMR deficiency and no detectable germline variants, are referred to as having Lynch-like syndrome. To investigate underlying and potentially predisposing variants related to Lynch-like syndrome, we performed whole-exome sequencing in patients with clinical criteria for Lynch syndrome, MMR deficiency and without germline variants. This approach allowed for the identification of new variants potentially associated with Lynch-like syndrome, providing new clues to explain the familial predisposition to Lynch syndrome-related tumors in these patients, which could lead to new screening strategies for the identification of families at risk of developing cancer. ABSTRACT: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes that lead to microsatellite instability. Patients who meet the clinical criteria for LS and MMR deficiency and without any identified germline pathogenic variants are frequently considered to have Lynch-like syndrome (LLS). These patients have a higher risk of CRC and extracolonic tumors, and little is known about their underlying genetic causes. We investigated the germline spectrum of LLS patients through whole-exome sequencing (WES). A total of 20 unrelated patients with MMR deficiency who met the clinical criteria for LS and had no germline variant were subjected to germline WES. Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) criteria. Pathogenic/likely pathogenic variants were identified in 35% of patients in known cancer genes such as MUTYH and ATM. Besides this, rare and potentially pathogenic variants were identified in the DNA repair gene POLN and other cancer-related genes such as PPARG, CTC1, DCC and ALPK1. Our study demonstrates the germline mutational status of LLS patients, a population at high risk of colorectal cancer.