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- W3136304458 abstract "ABSTRACT There is limited understanding of the epigenetic drivers of tumor evolution in hepatocellular carcinoma (HCC). We quantify epigenetic intra-tumoral heterogeneity (ITH) using regional enhanced reduced-representation bisulfite sequencing (eRRBS) DNA methylation data from 47 early stage, treatment-naive HCC biopsies across 9 patients. Integrating these data with matching RNAseq, targeted DNA sequencing, tumor-infiltrating lymphocyte (TIL) and hepatitis-B viral (HBV) expression, we computed regional differential methylation (DM) ITH signatures across 19,327 promoter regions, and 654,133 CpG islands, while overlapping with known methylation age marker genes (240/354). We found substantial ITH signatures in promoter and enhancer sites across 4/9 patients highlighting novel molecular pathways of tumor progression 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 evolution. In order to compute clinical associations with epigenetic tumoral age, we use 450k array data from 377 HCC patients in the TCGA-LIHC single-biopsy cohort to calculate tumoral age and find evidence implying that epigenetically old tumors have lower fitness yet higher TIL burden. Our data reveal a novel, unique epigenetic ITH axis in HCC tumors that furthers our understanding of tumor evolution and may serve as a potential avenue for enhancing patient stratification and treatment." @default.
- W3136304458 created "2021-03-29" @default.
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- W3136304458 date "2021-03-24" @default.
- W3136304458 modified "2023-09-23" @default.
- W3136304458 title "Intra-tumoral epigenetic heterogeneity and aberrant molecular clocks in hepatocellular carcinoma" @default.
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- W3136304458 doi "https://doi.org/10.1101/2021.03.22.21253654" @default.
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