{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T07:42:25Z","timestamp":1768549345507,"version":"3.49.0"},"posted":{"date-parts":[[2021,3,24]]},"group-title":"Oncology","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>There is limited understanding of the epigenetic drivers of tumor evolution in hepatocellular carcinoma (HCC). Here we characterize the epigenetic contribution of methylation to intra-tumoral heterogeneity (mITH) using regional enhanced reduced-representation bisulfite sequencing DNA methylation data from 47 early stage, treatment-naive HCC biopsies across 9 patients by quantifying regional differential methylation across promoters and CpG islands, while overlapping with methylation age markers. Furthermore, we integrate these data with matching RNA-sequencing, targeted DNA sequencing, tumor-infiltrating lymphocyte (TIL), and hepatitis-B viral expression data. We found substantial mITH signatures in promoter and enhancer sites across 44% of patients in our cohort that highlight a novel axis of ITH that is not otherwise detectable from RNA analysis alone. Additionally, we identify an epigenetic tumoral aging measure that reflects a complex tumor fitness phenotype as a potential proxy for tumor clonality. Associating clinical outcomes with epigenetic tumoral age using 450k array data from 377 patients with HCC in the TCGA-LIHC single-biopsy cohort we found evidence implying that epigenetically old tumors have lower fitness yet higher TIL burden. Our data reveal a novel, unique epigenetic axis of ITH in HCC that merits further exploration.<\/jats:p>","DOI":"10.1101\/2021.03.22.21253654","type":"posted-content","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T13:35:47Z","timestamp":1616592947000},"source":"Crossref","is-referenced-by-count":1,"title":["Intra-tumoral epigenetic heterogeneity and aberrant molecular clocks in hepatocellular carcinoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2045-2357","authenticated-orcid":false,"given":"Paula","family":"Restrepo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Bubie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda 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