Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticlepeer-review

523 Scopus citations

Abstract

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

Original languageEnglish (US)
Pages (from-to)1327-1341.e23
JournalCell
Volume169
Issue number7
DOIs
StatePublished - Jun 15 2017

Keywords

  • IDH1/2
  • TP53
  • cancer subtyping
  • expression profile
  • hepatocellular carcinoma
  • metabolic reprogramming
  • promoter hypermethylation
  • significantly mutated genes
  • sonic hedgehog signaling
  • stem cell phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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