Genomic and epigenomic architecture of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide.Understanding of the intratumoral heterogeneity of HCC is instructive for developingpersonalized therapy and molecular biomarkers. We applied whole exome sequencing to a total of58 samples from 10 patients to resolve the genetic architecture and subclonal diversification.Notably, spatial genomic diversity was found in all 10 HCC cases, with 33% of the drivermutations being heterogeneous. Temporal dissection of mutational signatures suggested thatexogenous and endogenous factors have different contributions in shaping the mutationalspectrum during the development of HCC. Moreover, we observed extensive intratumoralepigenetic heterogeneity in HCC, and showed that integrative analysis of both genetic andepigenetic phylogenies could generate more robust resolution of clonal architecture than singleprofiling approach. Our results also demonstrated prominent epigenetic subclonal diversificationeven in a stable HCC genome. Together, these findings highlight the widespread intratumoralheterogeneity at both genomic and epigenomic levels in HCC, and provide important molecularfoundation for better understanding of the biology and pathogenesis of this malignancy.