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PMID: 28622513 Published · ppublish English Journal Article

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma.

Cell ·Vol. 169 ·No. 7 ·2017-06-15 ·Pages 1327-1341.e23

Cancer Genome Atlas Research Network. Electronic address: [email protected], Cancer Genome Atlas Research Network

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
MeSH Terms
Carcinoma, Hepatocellular/genetics,virology DNA Methylation Genomics Humans Isocitrate Dehydrogenase/genetics Liver Neoplasms/genetics,virology MicroRNAs/genetics Mutation
Chemicals
MIRN122 microRNA, human MicroRNAs IDH2, human Isocitrate Dehydrogenase IDH1 protein, human
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Cancer Genome Atlas Research Network. Electronic address: [email protected]
Cancer Genome Atlas Research Network
Investigators
238 investigators, click to expand
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
Schumacher Steven E
Saksena Gordon
Pedamallu Chandra Sekhar
Chin Lynda
Getz Gad
Noble Michael
Zhang Hailei
Heiman David
Cho Juok
Gehlenborg Nils
Saksena Gordon
Voet Douglas
Lin Pei
Frazer Scott
Defreitas Timothy
Meier Sam
Lawrence Michael
Kim Jaegil
Creighton Chad J
Muzny Donna
Doddapaneni HarshaVardhan
Hu Jianhong
Wang Min
Morton Donna
Korchina Viktoriya
Han Yi
Dinh Huyen
Lewis Lora
Bellair Michelle
Liu Xiuping
Santibanez Jireh
Glenn Robert
Lee Sandra
Hale Walker
Parker Joel S
Wilkerson Matthew D
Hayes D Neil
Reynolds Sheila M
Shmulevich Ilya
Zhang Wei
Liu Yuexin
Iype Lisa
Makhlouf Hala
Torbenson Michael S
Kakar Sanjay
Yeh Matthew M
Jain Dhanpat
Kleiner David E
Jain Dhanpat
Dhanasekaran Renumathy
El-Serag Hashem B
Yim Sun Young
Weinstein John N
Mishra Lopa
Zhang Jianping
Akbani Rehan
Ling Shiyun
Ju Zhenlin
Su Xiaoping
Hegde Apurva M
Mills Gordon B
Lu Yiling
Chen Jian
Lee Ju-Seog
Sohn Bo Hwa
Shim Jae Jun
Tong Pan
Aburatani Hiroyuki
Yamamoto Shogo
Tatsuno Kenji
Li Wei
Xia Zheng
Stransky Nicolas
Seiser Eric
Innocenti Federico
Gao Jianjiong
Kundra Ritika
Zhang Hongxin
Heins Zachary
Ochoa Angelica
Sander Chris
Ladanyi Marc
Shen Ronglai
Arora Arshi
Sanchez-Vega Francisco
Schultz Nikolaus
Kasaian Katayoon
Radenbaugh Amie
Bissig Karl-Dimiter
Moore David D
Totoki Yasushi
Nakamura Hiromi
Shibata Tatsuhiro
Yau Christina
Graim Kiley
Stuart Josh
Haussler David
Slagle Betty L
Ojesina Akinyemi I
Katsonis Panagiotis
Koire Amanda
Lichtarge Olivier
Hsu Teng-Kuei
Ferguson Martin L
Demchok John A
Felau Ina
Sheth Margi
Tarnuzzer Roy
Wang Zhining
Yang Liming
Zenklusen Jean C
Zhang Jiashan
Hutter Carolyn M
Sofia Heidi J
Verhaak Roel G W
Zheng Siyuan
Lang Frederick
Chudamani Sudha
Liu Jia
Lolla Laxmi
Wu Ye
Naresh Rashi
Pihl Todd
Sun Charlie
Wan Yunhu
Benz Christopher
Perou Amy H
Thorne Leigh B
Boice Lori
Huang Mei
Rathmell W Kimryn
Noushmehr Houtan
Saggioro Fabiano Pinto
Tirapelli Daniela Pretti da Cunha
Junior Carlos Gilberto Carlotti
Mente Enio David
Silva Orlando de Castro
Trevisan Felipe Amstalden
Kang Koo Jeong
Ahn Keun Soo
Giama Nasra H
Moser Catherine D
Giordano Thomas J
Vinco Michelle
Welling Theodore H
Crain Daniel
Curley Erin
Gardner Johanna
Mallery David
Morris Scott
Paulauskis Joseph
Penny Robert
Shelton Candace
Shelton Troy
Kelley Robin
Park Joong-Won
Chandan Vishal S
Roberts Lewis R
Bathe Oliver F
Hagedorn Curt H
Auman J Todd
O'Brien Daniel R
Kocher Jean-Pierre A
Jones Corbin D
Mieczkowski Piotr A
Perou Charles M
Skelly Tara
Tan Donghui
Veluvolu Umadevi
Balu Saianand
Bodenheimer Tom
Hoyle Alan P
Jefferys Stuart R
Meng Shaowu
Mose Lisle E
Shi Yan
Simons Janae V
Soloway Matthew G
Roach Jeffrey
Hoadley Katherine A
Baylin Stephen B
Shen Hui
Hinoue Toshinori
Bootwalla Moiz S
Van Den Berg David J
Weisenberger Daniel J
Lai Phillip H
Holbrook Andrea
Berrios Mario
Laird Peter W
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2017.05.046
Published
2017-06-15
Pages
1327-1341.e23
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC5680778
Subset
IM
Grants
NIGMS NIH HHS · R01 GM079656 · United States
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · U24 CA143882 · United States
NHGRI NIH HHS · U54 HG003067 · United States
NCI NIH HHS · U24 CA143835 · United States
NIGMS NIH HHS · R01 GM066099 · United States
NCI NIH HHS · U24 CA143866 · United States
NCI NIH HHS · U24 CA210950 · United States
NCI NIH HHS · U24 CA143845 · United States
NCI NIH HHS · U24 CA143799 · United States
NHGRI NIH HHS · U54 HG003273 · United States
NCI NIH HHS · U24 CA144025 · United States
NCI NIH HHS · U24 CA143840 · United States
NCI NIH HHS · U24 CA143843 · United States
NCI NIH HHS · U24 CA143858 · United States
NCI NIH HHS · U24 CA143848 · United States
BLRD VA · I01 BX003732 · United States
NHGRI NIH HHS · U54 HG003079 · United States
NCI NIH HHS · U24 CA210949 · United States
NCI NIH HHS · U24 CA143883 · United States
NCI NIH HHS · U24 CA210999 · United States
NCI NIH HHS · U24 CA143867 · United States
NCI NIH HHS · U24 CA199461 · United States
NCI NIH HHS · U24 CA210990 · United States
Corrections
CommentIn
PMID: 28765583
CommentIn
PMID: 29312976
CommentIn
PMID: 29637589
External Links
PubMed source DOI: 10.1016/j.cell.2017.05.046 PMC Full Text View journal details
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