Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer

Abstract

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.

The association between methylation patterns of DNAH17 and clinicopathological factors in hepatocellular carcinoma

“…It was reported that 17q25.1‐3 copy number gain was a prognostic marker for poor patient survival in HCC . In liver cancer, the methylation‐correlated expression genes and DNA copy number‐correlated expression genes are significantly co‐regulated . We then explored the methylation status and copy number of DNAH17 in our cohort and noted that a lower methylation level of HCC samples was observed in DNAH17 amplification patients compared with the rest patients, which consisted with the data from TCGA data set.…”

“…27 In liver cancer, the methylation-correlated expression genes and DNA copy number-correlated expression genes are significantly co-regulated. 5 We then explored the methylation status and copy number of DNAH17 in our cohort and noted that a lower methylation level of HCC samples was observed in DNAH17 amplification patients compared with the rest patients, which consisted with the data from TCGA data set. This finding indicated that the DNAH17 overexpression in HCC tissue was possibly regulated by the synergy of gene amplification and hypomethylation.…”

“…Currently, aberrant methylation of tumor oncogenes and tumor suppressor genes has been noted in many cancers, leading to expression changes of cancer-related genes that promote tumorigenesis and progression. 4,5 Solid evidence revealed the significance of methylation deregulation in HCC. 4,6,7 Dynein, which is composed of several light, heavy, and intermediate chains, is an essential protein for the primary cilia.…”

Multiplatform Genomic Roadmap of Hepatocellular Carcinoma: A Matter of Molecular Heterogeneity

“…Multilayered genomic and epigenomic aberrations of these genes could identify three molecular subtypes. One of the subtypes was characterized by recurrent mutation of BAP1 , which is frequently mutated in iCCA, and concomitant expression of stem cell–like traits such as CA‐9 and KRT19 . These studies, along with the TCGA study, consistently suggest that the common features of HCC and iCCA play critical roles in acquisition of the aggressive HCC phenotype, linking their resemblance with bipotential stem cells that can differentiate into hepatocytes as well as cholangiocytes.…”

Vertical and horizontal integration of multi-omics data with miodin

“…In a study by Woo et al, DNA copy-number variation, methylation and gene expression were profiled in a cohort of hepatocellular carcinoma (HCC) patients. Integrative omics analysis revealed three molecular subtypes of HCC with differences in prognostic outcomes (5). Zhu et al performed a comprehensive pan-cancer integrative analysis showing that a combination of clinical variables with molecular profiles improves prognostic power in 7 of the 14 cancer types studied (6).…”