Comparison of clinical, pathological and genomic characteristics between Lynch and non-Lynch patients with MMRd endometrial carcinoma

Abstract Background Lynch syndrome (LS) is a common hereditary cancer predisposition syndrome caused by pathogenic germline mutations in MMR genes. This study aimed to conduct LS screening in a South Chinese Endometrial carcinoma (EC) cohort to identify hereditary mutation profiles. Methods Molecular classification was performed on 201 EC patients from South China. Sixty cases were identified as MMR deficiency (MMRd) EC. Tumor tissues from these MMRd EC cases were analyzed for MLH1 promoter methylation. Whole-exome sequencing (WES) of blood samples was conducted to detect germline mutations. Results There are certain differences among classification based solely on next-generation sequencing (NGS), classification based on the combination of NGS and IHC, and classification based solely on IHC. LS was diagnosed in 21.67% of patients with MMRd EC. Among patients showing MLH1 protein loss by IHC, 90.0% exhibited MLH1 promoter methylation. WES revealed that LS-associated pathogenic mutations predominantly involved MSH6 and MSH2, with MSH6 being the most frequent. Patients harboring MSH6 pathogenic mutations had a significantly older average age at EC diagnosis compared to those with MSH2 mutations (P = 0.014). Three newly identified pathogenic MMR gene mutations were identified among 13 LS patients. Conclusions Patients with adequate financial resources should undergo combined testing of microsatellite instability (MSI) status and MMR protein IHC. Patients with MLH1 promoter methylation, those with microsatellite stability (MSS), and those with serous carcinoma of the EC may all need to undergo LS screening.