Epigenetic Bridge Between Oxidative Balance of Koreans and TCGA Pan-Cancer Risk: Sex-Specific DNA Methylation Signatures

Oxidative stress is a hallmark of carcinogenesis, yet the epigenetic mechanisms linking the lifestyle-based Oxidative Balance Score (OBS) to cancer risk remain poorly understood. This study investigated the epigenetic bridge between OBS and pan-cancer susceptibility using a multi-cohort approach integrating population-based and cancer genomic data. We calculated OBS based on 16 dietary and lifestyle factors (including dietary fiber, vitamins, minerals, physical activity, smoking, alcohol, and BMI) for 2749 participants from the Korean Genome and Epidemiology Study (KoGES) and identified OBS-associated CpG sites via epigenome-wide association analysis. These markers were validated against The Cancer Genome Atlas (TCGA) pan-cancer dataset using a novel Hybrid Pi-score (HyPi) to quantify the directional consistency between OBS-driven methylation in healthy individuals and cancer-specific epigenetic alterations across three clinical comparisons: normal vs. tumor, survival outcomes, and tumor stage. We observed profound sex-specific epigenetic signatures, with zero overlap in the top 200 OBS-associated CpG sites between males and females, underscoring fundamental sexual dimorphism in oxidative stress-epigenome interactions. Notably, the top 20 OBS-associated CpGs demonstrated strong directional consistency with multiple cancer types in TCGA, particularly in kidney renal clear cell carcinoma and lung adenocarcinoma, exhibiting methylation patterns inversely correlated with tumorigenesis. Mechanistically, these findings support the role of one-carbon metabolism and vitamin C-dependent DNA demethylation pathways in mediating OBS effects. Our study provides the first evidence of an epigenetic link between lifestyle-based oxidative balance and pan-cancer risk, highlighting the utility of the HyPi score as a novel sex-specific predictive biomarker for cancer prevention. These results suggest that optimizing oxidative balance through precision nutrition may epigenetically modulate cancer susceptibility, opening new avenues for personalized prevention strategies.