Universal screening for Lynch syndrome and molecular classification of patients with endometrial cancer

Lynch syndrome (LS) is a cancer susceptibility syndrome characterized by a high risk table of multiple cancer types, most commonly endometrial cancer (EC). Currently, universal tumor screening to identify LS in women with EC remains uncommon. This study aimed to determine the incidence of LS and its molecular landscape by conducting a retrospective analysis of a cohort of patients with EC in China.

A total of 220 patients with EC were identified from the Hospital between March 2022 and May 2025. Germline variants in LS-associated genes ( MLH1, PMS2, MSH2, MSH6 , and EPCAM ) and molecular subtypes [ POLE, TP53 genes, and microsatellite instability (MSI)] were analyzed using next-generation sequencing (NGS). Mismatch repair (MMR) proteins were screened by immunohistochemistry (IHC). Tumors with loss of MLH1 or MLH1/PMS2 protein expression were tested for MLH1 promoter methylation.

Of the 220 cases, 16 (7.3%) had a pathogenic germline variant in MMR genes, with the majority identified in MSH6 ( n = 7), followed by MLH1 ( n = 3), PMS2 ( n = 3), and MSH2 ( n = 3). A total of 22 EC tumors (10.0%) carried a variant of uncertain significance in the LS-associated genes. Our results revealed that the percentages of the different molecular subtypes were POLE-mutated (POLEmut; 10.9%), mismatch repair deficient (MMRd; 25.5%), p53 abnormal (p53abn; 8.6%), and no specific molecular profile (NSMP; 55.0%). Ten "multiple-classifier" tumors (4.5% of the total cases) were identified. These included five MMRd-p53abn, four POLEmut-p53abn, and one POLE-MMRd.

This study confirms the effectiveness of NGS in identifying germline variants within a Chinese cohort of patients with EC, revealing an LS prevalence of 7.3%. Relying solely on MMR-IHC or MSI testing could lead to missed diagnoses of LS. Our findings contribute to a better understanding of the mutational landscape and prevalence of LS.