Distinct mutational landscape and clonal evolution of POLE-mutated endometrial cancer: geographic variation and insights into multiple classifier status.

BACKGROUND: POLE-mutated (POLEmut) endometrial cancer (EC) represents a distinct molecular subtype with a favorable prognosis. However, current knowledge is derived largely from Western-centric datasets, and population-specific differences in mutational landscapes remain insufficiently explored. In addition, the biological relevance of variant type and the evolutionary dynamics of rare tumors with concurrent POLEmut and microsatellite instability-high (MSI-H) are poorly understood. METHODS: We performed a comprehensive multi-cohort analysis by integrating the largest real-world dataset of POLEmut EC to date from a Chinese medical center (QDFY, n = 1,274) with public data from TCGA and CPTAC. Clinicopathological features, mutational spectra, and survival outcomes were compared across cohorts. In addition, multi-regional whole-exome sequencing was conducted to reconstruct the clonal architecture of a rare case harboring a concurrent POLE P286R mutation and MSI-H. RESULTS: In the QDFY cohort, we identified a distinct mutational profile in which the prevalence of the V411L variant (36.8%) was comparable to that of the P286R hotspot (37.6%). Notably, the favorable prognosis of POLEmut EC appeared consistent across ethnic backgrounds and variant types in our preliminary short-term follow-up, even in the presence of high-grade histology or concurrent TP53 mutations, which were enriched for the R213 nonsense variant. Evolutionary analysis of the rare POLE P286R/MSI-H case demonstrated that POLE P286R was a truncal event, whereas MSI-H arose as a subclonal event, providing a compelling hypothesis for the observed intratumoral heterogeneity. CONCLUSIONS: This study refines the molecular landscape of POLEmut EC by demonstrating a potentially high prevalence of the V411L variant in the Chinese population and showing that the favorable prognosis of POLEmut EC remains largely consistent across different ethnic backgrounds and specific hotspot mutations in this real-world cohort. These findings support universal POLE testing to avoid overtreatment and provide a hypothesis-generating basis for large-scale, multi-center studies with longer follow-up to validate the distinct mutational spectrum across diverse Chinese regions and confirm the long-term prognostic stability of cases with multiple molecular classifiers.