Integrated tumor and germline profiling of lynch syndrome in a North Indian cohort

Background: Lynch syndrome is the leading hereditary cause of colorectal and endometrial cancers, but data on germline mutations in the Indian population are insufficient. This study assessed patients with Lynch syndrome-related tumors using tumor mismatch repair (MMR) immunohistochemistry and/or microsatellite instability testing, followed by germline analysis of mismatch repair genes from blood samples. The goal was to determine the prevalence and molecular profile of Lynch syndrome in a North Indian population and to identify common pathogenic variants with high frequency in this population. Methods: We retrospectively evaluated 136 individuals with Lynch syndrome-associated malignancies or a strong personal or family history who were assessed at a tertiary cancer center in North India between January 2020 and February 2025. Tumor MMR status was determined by immunohistochemistry or by surrogate Microsatellite Instability testing. Germline analysis of MLH1, MSH2, MSH6, and PMS2 was performed using next-generation sequencing-based assays. Results: c.306G>T; p.(Glu102Asp), accounted for nearly one-quarter of Lynch syndrome cases and was observed exclusively in individuals of Punjabi ancestry, suggesting a strong founder effect. Conclusions: Lynch syndrome contributes substantially to colorectal and endometrial cancers in the North Indian population. MLH1 gene alterations predominate, and the presence of a founder variant is reaffirmed. 38.9% of reported cases are caused by LS. Germline testing helps identify probands and FDRs who are healthy mutation carriers. Risk-reduction strategies for them can help reduce the risk of CRC in the Indian population.