Cell
Volume 169, Issue 7, 15 June 2017, Pages 1327-1341.e23
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Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

https://doi.org/10.1016/j.cell.2017.05.046Get rights and content
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Highlights

  • Analysis of hepatocellular carcinomas integrates data of multiple genomic platforms

  • Mutated genes reveal oncogenic processes altering hepatocyte energy balance

  • Multiplex analyses suggest a key role for Sonic hedgehog signaling in HCC

  • IDH mutations point to a HCC subgroup molecularly similar to cholangiocarcinoma

Summary

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.

Keywords

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

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Lead Contact (David A. Wheeler)