Abstract 203P
Background
Hepatocellular carcinoma (HCC) is characterized by a spectrum of tumor heterogeneity from somatic mutations, rendering treatment difficult. Increasingly, epigenetic alterations within the non-coding genome are shown to play important roles in hepatocarcinogenesis and prognosis. We aimed to investigate the epigenetic promoter landscape of HCC and its etiologies, which remain poorly understood.
Methods
We recruited eligible HCC patients across 35 centers in 4 Southeast-Asian countries and followed them up prospectively. Resected tumor sectors were harvested with the adjacent normal liver tissues. Whole-genome transcriptomics were sequenced and profiled for differential gene expression between tumor and normal tissues, of varying etiologies. Correspondingly, chromatin immunoprecipitation sequencing (ChIP-Seq) of the trimethylated lysine K4 of histone H3 (H3K4me3), an epigenome marker for active promoters, was performed to identify differential H3K4me3 enrichment between the tumor and normal tissues. Hi-C was profiled on the samples to capture the three-dimensional chromatin landscape and distal gene interactions, for co-localization analysis with differential gene expression.
Results
From a cohort of 106 patients, we identified unique differential gene expression and epigenomic promoter signatures enriched with H3K4me3 in HCC vs. normal tissues. Moreover, gene ontological analysis revealed the enrichment of canonical cancer proliferative pathways in HCC compared to normal tissues. Notably, HCC of single etiology (hepatitis B or fatty liver) cluster separately from HCC of dual etiologies (hepatitis B and fatty liver), suggesting unique epigenetic dysregulations could exist in etiological subtypes that contribute to HCC. For the first time, we uncovered ectopic gain of distal intergenic H3K4me3-enriched regions unique in HCC, which were evinced to regulate and drive distal gene expression many kilobases away.
Conclusions
Aberrant epigenetic promoter signatures contribute to hepatocarcinogenesis, and the ectopic gain of distal intergenic promoters contributes to the aberrant gene expression in HCC. These present potential biomarkers and therapeutic targets for HCC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Singapore National Medical Research Council.
Disclosure
All authors have declared no conflicts of interest.