title: Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.
abstract: Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tatsuno
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Betty L
authors.initials: BL
authors.lastname: Slagle
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Lehmkuhl
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Walker
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Dahdouli
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Marie-Claude
authors.identifier: 0000000325706360
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.affiliation: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Midorikawa
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Goss
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Cotton
authors.affiliation: 1] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Shibahara
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jacfranz
authors.initials: J
authors.lastname: Guiteau
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Urushidate
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okada
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Harsha
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.affiliation: Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kokudo
authors.affiliation: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kosuge
authors.affiliation: Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: 1] Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. [2] Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
mesh_terms: D000465:Algorithms; D044466:Asian People; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D018899:CpG Islands; D004252:DNA Mutational Analysis; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D016679:Genome, Viral; D016174:Hepacivirus / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D007564:Japan; D008113:Liver Neoplasms / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D015233:Models, Statistical; D009154:Mutation; D025341:Principal Component Analysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D014481:United States; D044465:White People
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C509186:TERT protein, human; D019098:Telomerase