Intratumoral DNA Methylation Heterogeneity as a Determinant of Metastatic dissemination in Endometrial Cancer

DNA methylation heterogeneity represents a critical but largely underexplored layer of regulatory complexity in endometrial cancer (EC), with potential implications for tumor behavior and clinical outcome. Most studies rely on bulk-averaged methylation profiles, overlooking the spatial and clonal diversity of epigenetic states that may underlie differences in invasion, recurrence, and treatment resistance within the same molecular or histological subtype.

Here, we investigate whether endometrial tumors exhibit intratumoral methylation heterogeneity and uncover epigenetic mechanisms contributing to aggressiveness and dissemination. Through comprehensive methylation profiling of spatially distinct biopsies from primary tumors and matched metastatic lesions, we identified region-specific methylation patterns and CpG sites associated with metastatic progression. Thus, 39 CpG sites were significantly differentially methylated between primary tumors and metastases, impacting cancer-relevant pathways.