Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Dorothy Cheung, Tina WongDenise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Liu Xi, Kyle Covington, Eve Shinbrot, David A. Wheeler, Richard A. Gibbs, Lawrence A. Donehower, Linghua Wang, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Bradley A. Murray, Juliann Shih, Rameen Beroukhim, Andrew D. Cherniack, Steven E. Schumacher, Nasra H. Giama, The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticlepeer-review

540 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

Bibliographical note

Funding Information:
We are grateful to the patients who contributed to this study. This work was?supported by these grants from the U.S. NIH: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, and P30CA16672.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

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

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