Epigenetic dispositions in ovarian clear cell carcinoma: a nexus of genomic, epigenetic, and metabolic alterations

Ovarian clear cell carcinoma (CCC) is a highly aggressive malignancy characterized by poor prognosis due to its resistance to chemotherapy, particularly in the advanced stages. This neoplasm originates from endometriotic cysts containing high levels of iron, derived from blood. This accumulation of iron generates oxidative stress, leading to DNA damage and carcinogenesis. Genomic analyses have identified frequent mutations in ARID1A and PIK3CA, which are also present in normal endometrial gland cells, suggesting that the cells originated from normal endometrium. A unique gene expression profile, termed the OCCC signature, is characterized by the upregulation of HNF1B signaling and oxidative stress-related genes. These genes are induced by the stressful microenvironment of endometriotic cysts. Comprehensive DNA methylation analysis has revealed that ovarian CCC exhibits a distinct epigenetic landscape, marked by global hypomethylation of HNF1B-related transcriptional signals, resulting in their activation. Functionally, ovarian CCC is characterized by enhanced anaerobic metabolism, mitochondrial dysfunction, and resistance to ferroptosis, an iron-dependent form of cell death. Notably, the suppression of HNF1B has been associated with increased sensitivity to chemotherapy, highlighting its role in drug resistance. These findings suggest that ovarian CCC develops through epigenomic carcinogenesis, wherein chronic oxidative stress in endometriotic cysts drives epigenetic alterations that promote tumor formation and therapeutic resistance, representing “epigenetic dispositions”. The elucidation of these mechanisms may provide novel insights into potential therapeutic targets to overcome the aggressive behaviors of ovarian CCC.