{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:05:59Z","timestamp":1790813159948,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Global-Learning & Academic research institution for Master\u2019s\u2013PhD students"},{"DOI":"10.13039\/501100003725","name":"Postdocs (G-LAMP) Program of the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education","doi-asserted-by":"publisher","award":["RS-2025-25441283"],"award-info":[{"award-number":["RS-2025-25441283"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea","award":["RS-2025-02213601"],"award-info":[{"award-number":["RS-2025-02213601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/antiox15030386","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T11:50:36Z","timestamp":1773921036000},"page":"386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetic Bridge Between Oxidative Balance of Koreans and TCGA Pan-Cancer Risk: Sex-Specific DNA Methylation Signatures"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8843-6006","authenticated-orcid":false,"given":"Sun-Young","family":"Kang","sequence":"first","affiliation":[{"name":"Institute for Molecular Metabolism Innovation, Soonchunhyang University, Asan 31538, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Soo","family":"Gim","sequence":"additional","affiliation":[{"name":"Department of Pet Health Care, Busan Health University, Busan 49318, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8064-7880","authenticated-orcid":false,"given":"Hyunbin","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Companion Animal Health, Tongmyong University, Busan 48520, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-An","family":"Gim","sequence":"additional","affiliation":[{"name":"Institute for Molecular Metabolism Innovation, Soonchunhyang University, Asan 31538, Republic of Korea"},{"name":"Department of Medical Science, Soonchunhyang University, Asan 31538, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents","volume":"21","author":"Sies","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ccell.2020.06.001","article-title":"Oxidative Stress in Cancer","volume":"38","author":"Hayes","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.2174\/1381612825666190215121712","article-title":"Oxidative Stress and Cancer","volume":"24","author":"Klaunig","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.freeradbiomed.2010.09.006","article-title":"Oxidative stress, inflammation, and cancer: How are they linked?","volume":"49","author":"Reuter","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.freeradbiomed.2011.05.018","article-title":"Clinical trials of antioxidants as cancer prevention agents: Past, present, and future","volume":"51","author":"Goodman","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nrd4002","article-title":"Modulation of oxidative stress as an anticancer strategy","volume":"12","author":"Gorrini","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1111\/j.1749-6632.2000.tb06498.x","article-title":"Body Composition in Healthy Aging","volume":"904","author":"Baumgartner","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1093\/aje\/kwu318","article-title":"Oxidative Balance Scores and Risk of Incident Colorectal Cancer in a US Prospective Cohort Study","volume":"181","author":"Dash","year":"2015","journal-title":"Am. J. Epidemiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/ijc.32870","article-title":"Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study","volume":"147","author":"Jakszyn","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lin, F., Zhou, R., Ou, Q., Tu, K., Fang, Y., and Zhang, C. (2025). Oxidative Balance Score Calculated Using Different Methods and Its Associations with Colorectal Cancer Risk. Nutrients, 17.","DOI":"10.3390\/nu17040679"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Moon, M.E., Jung, D.H., Heo, S.J., Park, B., and Lee, Y.J. (2024). Oxidative Balance Score and New-Onset Type 2 Diabetes Mellitus in Korean Adults without Non-Alcoholic Fatty Liver Disease: Korean Genome and Epidemiology Study-Health Examinees (KoGES-HEXA) Cohort. Antioxidants, 13.","DOI":"10.3390\/antiox13010107"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ke, R., He, Y., and Chen, C. (2023). Association between oxidative balance score and kidney stone in United States adults: Analysis from NHANES 2007\u20132018. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1275750"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA Methylation and Its Basic Function","volume":"38","author":"Moore","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2217\/epi.09.33","article-title":"DNA Hypomethylation in Cancer Cells","volume":"1","author":"Ehrlich","year":"2009","journal-title":"Epigenomics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41580-019-0159-6","article-title":"The diverse roles of DNA methylation in mammalian development and disease","volume":"20","author":"Greenberg","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrg3142","article-title":"Epigenetics and the environment: Emerging patterns and implications","volume":"13","author":"Feil","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1146\/annurev-publhealth-040617-014629","article-title":"Environmental Influences on the Epigenome: Exposure-Associated DNA Methylation in Human Populations","volume":"39","author":"Martin","year":"2018","journal-title":"Annu. Rev. Public Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1093\/ije\/dyv316","article-title":"Cohort Profile: The Korean Genome and Epidemiology Study (KoGES) Consortium","volume":"46","author":"Kim","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41585-019-0211-5","article-title":"The Cancer Genome Atlas of renal cell carcinoma: Findings and clinical implications","volume":"16","author":"Linehan","year":"2019","journal-title":"Nat. Rev. Urol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nature13385","article-title":"Comprehensive molecular profiling of lung adenocarcinoma","volume":"511","year":"2014","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1093\/bioinformatics\/bts170","article-title":"Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions","volume":"28","author":"Teschendorff","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1093\/bioinformatics\/btr671","article-title":"A novel significance score for gene selection and ranking","volume":"30","author":"Xiao","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_25","unstructured":"R Core Team (2000). R: A Language and Environment for Statistical Computing, R Core Team."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrc.2016.30","article-title":"Sexual dimorphism in cancer","volume":"16","author":"Clocchiatti","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41568-021-00348-y","article-title":"Sex disparities matter in cancer development and therapy","volume":"21","author":"Haupt","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13072-015-0035-3","article-title":"Characterization of whole-genome autosomal differences of DNA methylation between men and women","volume":"8","author":"Singmann","year":"2015","journal-title":"Epigenetics Chromatin"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10715762.2019.1702656","article-title":"Hormones and oxidative stress: An overview","volume":"54","author":"Chainy","year":"2019","journal-title":"Free Radic. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s10545-010-9128-0","article-title":"Folate and cancer: How DNA damage, repair and methylation impact on colon carcinogenesis","volume":"34","author":"Duthie","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mahmoud, A.M., and Ali, M.M. (2019). Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome. Nutrients, 11.","DOI":"10.3390\/nu11030608"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1146\/annurev-nutr-071714-034228","article-title":"Regulation of the Epigenome by Vitamin C","volume":"35","author":"Young","year":"2015","journal-title":"Annu. Rev. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.impact.2017.01.001","article-title":"Oxidative stress, DNA methylation, and telomere length changes in peripheral blood mononuclear cells after pulmonary exposure to metal-rich welding nanoparticles","volume":"5","author":"Shoeb","year":"2017","journal-title":"NanoImpact"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/3\/386\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:11:05Z","timestamp":1773922265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/3\/386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["antiox15030386"],"URL":"https:\/\/doi.org\/10.3390\/antiox15030386","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}