Integrated Molecular Profiling of Endometrial Cancer: NGS Findings, MSI/MMR Status, Histopathological Features, and...

Background/Objectives: Endometrial cancer is a heterogeneous malignancy that displays distinct molecular features and clinical behaviors. The molecular profile of endometrial cancer and its relationship with menopausal status, histological subtype, tumor grade, mismatch repair (MMR)/microsatellite instability (MSI) status, co-mutation patterns, and TCGA molecular classification were investigated in the current study. Methods: A total of 81 histopathologically confirmed endometrial cancer cases were retrospectively evaluated. Molecular profiling was performed using a targeted 71-gene NGS panel together with MSI-PCR and mismatch repair (MMR) immunohistochemistry. Because the targeted panel was not designed to detect genome-wide copy-number alterations or comprehensive mutational signatures, molecular subgroup assignment was performed using a surrogate TCGA-inspired molecular classification approach based on POLE mutation status, microsatellite instability (MSI)/Mismatch Repair (MMR) findings, and TP53 alterations. Histological subtypes, tumor grades, menopausal status, and molecular alterations were compared. Results: Of the cases evaluated, 57 (70.4%) were endometrioid and 24 (29.6%) were serous carcinoma. TP53 variations were significantly higher in serous carcinomas compared to endometrioid tumors (66.7% vs. 26.3%; p = 0.001). In endometrioid carcinomas, the mean number of variants increased with advancing tumor grade (Grade 1: 4.44; Grade 2: 9.68; Grade 3: 11.42; p = 0.006). Alterations in BLM, CDC27, MLH3, and MSH3 were more frequently observed in high-grade tumors. In exploratory analyses, no significant differences were detected between the premenopausal and postmenopausal groups regarding total variant load, number of altered genes, MSI status, or the distribution of TCGA-inspired molecular subgroups; however, these comparisons were limited by the small number of premenopausal patients. The most frequent co-mutation was observed between BLM and CDC27 (55.6%). In the TCGA-inspired molecular classification, the most prevalent subgroup was NSMP-proxy (33.3%). Conclusions: Serous and endometrioid endometrial cancers display distinct molecular characteristics. In endometrioid carcinomas, the genomic alteration load increases in parallel with advancing tumor grade. TCGA-inspired molecular classification and co-mutation analyses revealed the prominent molecular heterogeneity of endometrial cancer. In exploratory analyses, no significant differences were detected between the premenopausal and postmenopausal groups regarding total variant load, number of altered genes, MSI status, or the distribution of TCGA-inspired molecular subgroups. However, these findings should be interpreted with caution because of the limited number of premenopausal patients. Given the limited number of premenopausal patients, findings related to menopausal status should be considered exploratory and require validation in larger, independent cohorts.