肝细胞癌中的瘤内表观遗传异质性与异常分子钟

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.