Hepatocellular carcinoma harbors numerous genomic and epigenomic aberrations of DNA copy numbers and DNA methylation. Transcriptomic deregulation by these aberrations plays key driver roles in heterogeneous progression of cancers. Here, we profile DNA copy numbers, DNA methylation, and messenger RNA expression levels from 64 cases of hepatocellular carcinoma specimens. We find that the frequencies of the aberrancies of the DNA copy-number-correlated (CNVcor) expression genes and the methylation-correlated expression (METcor) genes are co-regulated significantly. Multi-omics integration of the CNVcor and METcor genes reveal three prognostic subtypes of hepatocellular carcinoma, which can be validated by an independent data. The most aggressive subtype expressing stemness genes has frequent BAP1 mutations, implying its pivotal role in the aggressive tumor progression. In conclusion, our integrative analysis of genomic and epigenomic regulation provides new insights on the multi-layered pathobiology of hepatocellular carcinoma, which might be helpful in developing precision management for hepatocellular carcinoma patients.
Recent large-scale and multi-omics profiling of cancers has provided a systematic picture of genomic and epigenomic deregulation in these diseases. Genomic alterations due to DNA copy-number aberration or mutations occur frequently during tumorigenesis, stimulating cancer progression. Epigenetic regulation of the cancer genome by DNA methylation also plays pivotal roles in heterogeneous cancer behaviors. In particular, in hepatocellular carcinoma (HCC), genomic profiling studies have demonstrated the enormous heterogeneity of genomic and epigenomic deregulation1. In this cancer, aberrations of DNA copy number play key regulatory roles in HCC progression2,3,4, and transcriptional deregulation resulting from such aberrations is a potential driver event in HCC progression5, 6. In addition, DNA methylation profiling studies have revealed the biological and clinical significance of epigenetic regulation in HCC progression7,8,9,10,11. Several key cancer-related genes such as IGF212 and UHRF113 exert their regulatory functions by modulating DNA methylation.
However, despite the genome-wide impact of aberrations of DNA copy numbers and DNA methylation on cancers, it remains unclear whether DNA copy-number aberration is systematically related to epigenetic DNA methylations, and, if so, whether this connection plays any role in cancer progression. In this study, we profiled DNA copy numbers, DNA methylation, and messenger RNA (mRNA) expression levels in a cohort of HCC patients. To identify genes whose expression levels are regulated by genomic and/or epigenomic deregulation, we defined DNA copy-number-correlated (CNVcor) and DNA methylation-correlated (METcor) genes, based on their corresponding gene expression levels across samples, respectively. CNVcor genes represent the transcriptional deregulation dependent on DNA copy number, whereas METcor genes represent transcriptional deregulation dependent on DNA methylation. Expression of CNVcor genes was significantly correlated with expression of METcor genes, suggesting concomitant regulation of cancer transcriptomes by alterations in genomic DNA copy number in addition to epigenetic DNA methylation. Moreover, by performing multi-omics integration of CNVcor and METcor genes, we could identify distinct molecular subtypes that were significantly associated with prognostic outcomes of HCC. Further systematic analysis could identify new mutations that could be used as precision targets or biomarkers for subtype distinction.