Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers

Simple Summary The most prevalent type of hereditary colorectal cancer is called Lynch syndrome and it is characterized by a tumor phenotype called microsatellite instability (MSI). This disease is a consequence of germline (inheritable) variants in any of the four mismatch repair (MMR) DNA genes, being their identification essential to ensure their appropriate diagnosis and implementation of preventive measurements. Nevertheless, only 50% of patients with MSI and suspected Lynch syndrome actually carry a germline pathogenic variant in an MMR gene that explains the clinical entity. The remaining 50% are termed Lynch-like syndrome, and their causes remain unknown. In this work, we tried to elucidate the molecular mechanisms that underlie this rare entity in a group of early-onset Lynch-like syndrome colorectal cancer, through whole-exome sequencing of germline and tumor samples. We observed that one-third of these patients have somatic alterations in genes associated with the MMR system and that these could be the mechanism causing their unexplained MSI. Furthermore, we found that patients who showed biallelic somatic alterations also carried germline variants in new candidate genes associated with DNA repair functions and that this could be, partly, the cause of the early onset in this cohort. Abstract Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.