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 Wong & 31 others Denise 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, Gordon B. Mills, Zheng Xia, The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages1327-1341.e23
JournalCell
Volume169
Issue number7
DOIs
StatePublished - Jun 15 2017

Fingerprint

Hepatocellular Carcinoma
Genes
DNA
MicroRNAs
Gene expression
Liver
DNA Sequence Analysis
RNA
Exome
Mutation
p53 Genes
DNA Methylation
Liver Neoplasms
Proteins
Transcriptome
Proteomics
Cluster Analysis
Down-Regulation
Mortality
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ally, A., Balasundaram, M., Carlsen, R., Chuah, E., Clarke, A., Dhalla, N., ... The Cancer Genome Atlas Research Network (2017). Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 169(7), 1327-1341.e23. DOI: 10.1016/j.cell.2017.05.046

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

In: Cell, Vol. 169, No. 7, 15.06.2017, p. 1327-1341.e23.

Research output: Contribution to journalArticle

Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Clarke, A, Dhalla, N, Holt, RA, Jones, SJM, Lee, D, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Cheung, D, Wong, T, Brooks, D, Robertson, AG, Bowlby, R, Mungall, K, Sadeghi, S, Xi, L, Covington, K, Shinbrot, E, Wheeler, DA, Gibbs, RA, Donehower, LA, Wang, L, Bowen, J, Gastier-Foster, JM, Gerken, M, Helsel, C, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Gabriel, SB, Meyerson, M, Cibulskis, C, Murray, BA, Shih, J, Beroukhim, R, Cherniack, AD, Mills, GB, Xia, Z & The Cancer Genome Atlas Research Network 2017, 'Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma' Cell, vol. 169, no. 7, pp. 1327-1341.e23. DOI: 10.1016/j.cell.2017.05.046
Ally A, Balasundaram M, Carlsen R, Chuah E, Clarke A, Dhalla N et al. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017 Jun 15;169(7):1327-1341.e23. Available from, DOI: 10.1016/j.cell.2017.05.046
Ally, Adrian ; Balasundaram, Miruna ; Carlsen, Rebecca ; Chuah, Eric ; Clarke, Amanda ; Dhalla, Noreen ; Holt, Robert A. ; Jones, Steven J.M. ; Lee, Darlene ; Ma, Yussanne ; Marra, Marco A. ; Mayo, Michael ; Moore, Richard A. ; Mungall, Andrew J. ; Schein, Jacqueline E. ; Sipahimalani, Payal ; Tam, Angela ; Thiessen, Nina ; Cheung, Dorothy ; Wong, Tina ; Brooks, Denise ; Robertson, A. Gordon ; Bowlby, Reanne ; Mungall, Karen ; Sadeghi, Sara ; Xi, Liu ; Covington, Kyle ; Shinbrot, Eve ; Wheeler, David A. ; Gibbs, Richard A. ; Donehower, Lawrence A. ; Wang, Linghua ; Bowen, Jay ; Gastier-Foster, Julie M. ; Gerken, Mark ; Helsel, Carmen ; Leraas, Kristen M. ; Lichtenberg, Tara M. ; Ramirez, Nilsa C. ; Wise, Lisa ; Zmuda, Erik ; Gabriel, Stacey B. ; Meyerson, Matthew ; Cibulskis, Carrie ; Murray, Bradley A. ; Shih, Juliann ; Beroukhim, Rameen ; Cherniack, Andrew D. ; Mills, Gordon B. ; Xia, Zheng ; The Cancer Genome Atlas Research Network. / Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. In: Cell. 2017 ; Vol. 169, No. 7. pp. 1327-1341.e23
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