Genomic analysis of liver cancer unveils novel driver genes and distinct prognostic features

Theranostics. 2018 Feb 12;8(6):1740-1751. doi: 10.7150/thno.22010. eCollection 2018.


Objective: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with a dismal prognosis. However, driver genes and prognostic markers in HCC remain to be identified. It is hoped that in-depth analysis of HCC genomes in relation to available clinicopathological information will give rise to novel molecular prognostic markers. Methods: We collected genomic data of 1,061 HCC patients from previous studies, and performed integrative analysis to identify significantly mutated genes and molecular prognosticators. We employed three MutSig algorithms (MutSigCV, MutSigCL and MutSigFN) to identify significantly mutated genes. The GISTIC2 algorithm was used to delineate focally amplified and deleted genomic regions. Nonnegative matrix factorization (NMF) was utilized to decipher mutational signatures. Kaplan-Meier survival and Cox regression analyses were used to associate gene mutation and copy number alteration with survival outcome. Logistic regression model was applied to test association between gene mutation and mutational signatures. Results: We discovered 11 novel driver genes, including RNF213, VAV3 and TNRC6B, with mutational prevalence ranging from 1% to 3%. Seven mutational signatures were also identified in HCC, some of which were associated with mutations of classical driver genes (e.g., TP53, TERT) as well as alcohol consumption. Focal amplifications of TERT and other druggable targets, including AURKA, were also revealed. Targeting AURKA by a small-molecule inhibitor potently induced apoptosis in HCC cells. We further demonstrated that HCC patients with TERT amplification displayed shortened overall survival independent of other clinicopathological parameters. In conclusion, our study identified novel cancer driver genes and prognostic markers in HCC, reiterating the translational importance of omics data in the precision medicine era.

Keywords: HCC; TERT; druggable target; mutation; prognostic marker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Aurora Kinase A / genetics
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Hepatocellular / diagnosis
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Computational Biology
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Kaplan-Meier Estimate
  • Liver Neoplasms / diagnosis
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Mutation*
  • Neoplasm Proteins / genetics*
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins c-vav / genetics
  • RNA-Binding Proteins / genetics
  • Telomerase / genetics
  • Ubiquitin-Protein Ligases / genetics


  • Biomarkers, Tumor
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-vav
  • RNA-Binding Proteins
  • TNRC6B protein, human
  • VAV3 protein, human
  • RNF213 protein, human
  • Ubiquitin-Protein Ligases
  • AURKA protein, human
  • Aurora Kinase A
  • TERT protein, human
  • Telomerase
  • Adenosine Triphosphatases