Real-world genomic profiling of endometrial cancer in south India to identify clinically actionable alterations.

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Background: Endometrial cancer exhibits substantial molecular heterogeneity with important implications for prognosis and therapeutic selection. While TCGA has defined distinct molecular subgroups, real-world data integrating next-generation sequencing (NGS) to identify actionable alterations and pathway-level dependencies remain limited. This study aimed to characterize the mutational landscape of endometrial cancer using targeted NGS and to evaluate clinically relevant genomic alterations that may inform precision oncology strategies. Methods: A total of 64 endometrial cancer samples were subjected to targeted NGS using a comprehensive oncology panel covering key cancer-related genes. High-quality genomic DNA was extracted, libraries were prepared, and sequencing was performed on an Illumina platform. Bioinformatic analysis included variant calling for single-nucleotide variants and small insertions/deletions, followed by clinical annotation according to ACMG/AMP and ASCO/CAP guidelines. Identified alterations were correlated at gene, pathway, and molecular subgroup levels, including inference of TCGA molecular classes. Results: Somatic mutations were detected across multiple oncogenic pathways. The PI3K–AKT–mTOR pathway was the most frequently altered, with PTEN mutations in 51.6% and PIK3CA mutations in 31.3% of cases. TP53 alterations were identified in 17.2%, consistent with an aggressive molecular subset. Alterations in FGFR2 and KRAS were each observed in 14.1% of cases, highlighting RAS–MAPK pathway involvement. DNA damage response alterations included POLE mutations (6.3%) and MMR gene alterations (MLH1/PMS2, ~6–7%), supporting molecular stratification relevant to immunotherapy. Overall, the cohort was predominantly classified as no specific molecular profile (NSMP), followed by TP53-aberrant, MMR-deficient, and POLE-ultramutated subgroups. Conclusions: Targeted NGS revealed a high prevalence of actionable genomic alterations in endometrial cancer, predominantly driven by PI3K–AKT–mTOR pathway dysregulation. Molecular subclassification identified clinically relevant subsets with potential implications for targeted therapy and immunotherapy selection. These findings support the integration of routine NGS-based profiling into endometrial cancer management to enable precision-guided therapeutic decision-making in real-world clinical settings.