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Cell. 2017 Jun 15;169(7):1327-1341.e23. doi: 10.1016/j.cell.2017.05.046.

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma.

Collaborators (238)

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, Schumacher SE, Saksena G, Pedamallu CS, Chin L, Getz G, Noble M, Zhang H, Heiman D, Cho J, Gehlenborg N, Saksena G, Voet D, Lin P, Frazer S, Defreitas T, Meier S, Lawrence M, Kim J, Creighton CJ, Muzny D, Doddapaneni H, Hu J, Wang M, Morton D, Korchina V, Han Y, Dinh H, Lewis L, Bellair M, Liu X, Santibanez J, Glenn R, Lee S, Hale W, Parker JS, Wilkerson MD, Hayes DN, Reynolds SM, Shmulevich I, Zhang W, Liu Y, Iype L, Makhlouf H, Torbenson MS, Kakar S, Yeh MM, Jain D, Kleiner DE, Jain D, Dhanasekaran R, El-Serag HB, Yim SY, Weinstein JN, Mishra L, Zhang J, Akbani R, Ling S, Ju Z, Su X, Hegde AM, Mills GB, Lu Y, Chen J, Lee JS, Sohn BH, Shim JJ, Tong P, Aburatani H, Yamamoto S, Tatsuno K, Li W, Xia Z, Stransky N, Seiser E, Innocenti F, Gao J, Kundra R, Zhang H, Heins Z, Ochoa A, Sander C, Ladanyi M, Shen R, Arora A, Sanchez-Vega F, Schultz N, Kasaian K, Radenbaugh A, Bissig KD, Moore DD, Totoki Y, Nakamura H, Shibata T, Yau C, Graim K, Stuart J, Haussler D, Slagle BL, Ojesina AI, Katsonis P, Koire A, Lichtarge O, Hsu TK, Ferguson ML, Demchok JA, Felau I, Sheth M, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Hutter CM, Sofia HJ, Verhaak RGW, Zheng S, Lang F, Chudamani S, Liu J, Lolla L, Wu Y, Naresh R, Pihl T, Sun C, Wan Y, Benz C, Perou AH, Thorne LB, Boice L, Huang M, Rathmell WK, Noushmehr H, Saggioro FP, Tirapelli DPDC, Junior CGC, Mente ED, Silva OC Jr, Trevisan FA, Kang KJ, Ahn KS, Giama NH, Moser CD, Giordano TJ, Vinco M, Welling TH, Crain D, Curley E, Gardner J, Mallery D, Morris S, Paulauskis J, Penny R, Shelton C, Shelton T, Kelley R, Park JW, Chandan VS, Roberts LR, Bathe OF, Hagedorn CH, Auman JT, O'Brien DR, Kocher JA, Jones CD, Mieczkowski PA, Perou CM, Skelly T, Tan D, Veluvolu U, Balu S, Bodenheimer T, Hoyle AP, Jefferys SR, Meng S, Mose LE, Shi Y, Simons JV, Soloway MG, Roach J, Hoadley KA, Baylin SB, Shen H, Hinoue T, Bootwalla MS, Van Den Berg DJ, Weisenberger DJ, Lai PH, Holbrook A, Berrios M, Laird PW.

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.

KEYWORDS:

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

PMID:
28622513
PMCID:
PMC5680778
DOI:
10.1016/j.cell.2017.05.046
[Indexed for MEDLINE]
Free PMC Article

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