Novel insights into the molecular heterogeneity of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is influenced by numerous factors, which results in diverse genetic, epigenetic and transcriptional scenarios, thus posing obvious challenges for disease management. We scrutinized the molecular heterogeneity of HCC with a multi-omics approach in two small cohorts of resected and explanted livers. Whole-genome transcriptomics was conducted, including polyadenylated transcripts and micro (mi)-RNAs. Copy number variants (CNV) were inferred from whole genome low-pass sequencing data. Fifty-six cancer-related genes were screened using an oncology panel assay. HCC was associated with a dramatic transcriptional deregulation of hundreds of protein-coding genes suggesting downregulation of drugs catabolism, induction of inflammatory responses, and increased cell proliferation in resected livers. Moreover, several long non-coding RNAs and miRNAs not reported previously in the context of HCC were found deregulated. In explanted livers, downregulation of genes involved in energy-producing processes and upregulation of genes aiding in glycolysis were detected. Numerous CNV events were observed, with conspicuous hotspots on chromosomes 1 and 17. Amplifications were more common than deletions, and spanned regions containing genes potentially involved in tumorigenesis. CSF1R, FGFR3, FLT3, NPM1, PDGFRA, PTEN, SMO and TP53 were mutated in all tumors, while other 26 cancer-related genes were mutated with variable penetrance. Our results highlight a remarkable molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are urgently needed for cancer treatment. We expect that our results will serve as a valuable dataset that will generate hypotheses for us or other researchers to evaluate to ultimately improve our understanding of HCC biology.

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“…In this disease, genetic alterations cause transformation of normal hepatocytes into tumor cells. [5] Some of the major risk factors for the development of pathology are consumption of alcohol, hepatitis B virus (HBV), hepatitis C virus infection, liver cirrhosis, and carcinogenic agents. Out of the abovementioned factors, chronic HBV infection is the leading cause of liver carcinogenesis in Asian countries which accounts for 75% cases per annum.…”

Role of exosomal competing endogenous RNA in patients with hepatocellular carcinoma

“…Integration of genomics and epigenomics has drawn much attention in many research works to clarify the molecular heterogeneity of HCC . More molecular studies on HCC biomarkers and therapeutic drug targets are needed to improve patients’ outcomes …”

“…5 More molecular studies on HCC biomarkers and therapeutic drug targets are needed to improve patients' outcomes. 6 Studies are not only limited to protein-coding genes but also extend to several classes of structurally and functionally different noncoding RNAs. 7,8 Long noncoding RNA exosomes were previously considered as cellular debris; however, they are currently well-recognized vectors for intercellular exchange of information.…”