TY - JOUR
T1 - Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma
AU - The Cancer Genome Atlas Research Network
AU - Ally, Adrian
AU - Balasundaram, Miruna
AU - Carlsen, Rebecca
AU - Chuah, Eric
AU - Clarke, Amanda
AU - Dhalla, Noreen
AU - Holt, Robert A.
AU - Jones, Steven J.M.
AU - Lee, Darlene
AU - Ma, Yussanne
AU - Marra, Marco A.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Mungall, Andrew J.
AU - Schein, Jacqueline E.
AU - Sipahimalani, Payal
AU - Tam, Angela
AU - Thiessen, Nina
AU - Cheung, Dorothy
AU - Wong, Tina
AU - Brooks, Denise
AU - Robertson, A. Gordon
AU - Bowlby, Reanne
AU - Mungall, Karen
AU - Sadeghi, Sara
AU - Xi, Liu
AU - Covington, Kyle
AU - Shinbrot, Eve
AU - Wheeler, David A.
AU - Gibbs, Richard A.
AU - Donehower, Lawrence A.
AU - Wang, Linghua
AU - Bowen, Jay
AU - Gastier-Foster, Julie M.
AU - Gerken, Mark
AU - Helsel, Carmen
AU - Leraas, Kristen M.
AU - Lichtenberg, Tara M.
AU - Ramirez, Nilsa C.
AU - Wise, Lisa
AU - Zmuda, Erik
AU - Gabriel, Stacey B.
AU - Meyerson, Matthew
AU - Cibulskis, Carrie
AU - Murray, Bradley A.
AU - Shih, Juliann
AU - Beroukhim, Rameen
AU - Cherniack, Andrew D.
AU - Mills, Gordon B.
AU - Xia, Zheng
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - 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.
AB - 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.
KW - IDH1/2
KW - TP53
KW - cancer subtyping
KW - expression profile
KW - hepatocellular carcinoma
KW - metabolic reprogramming
KW - promoter hypermethylation
KW - significantly mutated genes
KW - sonic hedgehog signaling
KW - stem cell phenotype
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U2 - 10.1016/j.cell.2017.05.046
DO - 10.1016/j.cell.2017.05.046
M3 - Article
C2 - 28622513
AN - SCOPUS:85020833799
SN - 0092-8674
VL - 169
SP - 1327-1341.e23
JO - Cell
JF - Cell
IS - 7
ER -