Yasushi Totoki1, 14, Kenji Tatsuno2, 14, Kyle R. Covington3, 14, Hiroki Ueda2, Chad J. Creighton3, 4, Mamoru Kato1, Shingo Tsuji2, Lawrence A. Donehower5, Betty L. Slagle5, Hiromi Nakamura1, Shogo Yamamoto2, Eve Shinbrot3, Natsuko Hama1, Megan Lehmkuhl3, Fumie Hosoda1, Yasuhito Arai1, Kim Walker3, Mahmoud Dahdouli3, Kengo Gotoh2, Genta Nagae2, Marie-Claude Gingras3, Donna M. Muzny3, Hidenori Ojima6, Kazuaki Shimada7, Yutaka Midorikawa8, John A. Goss9, Ronald Cotton9, Akimasa Hayashi2, 10, Junji Shibahara10, Shumpei Ishikawa10, Jacfranz Guiteau9, Mariko Tanaka10, Tomoko Urushidate1, Shoko Ohashi1, Naoko Okada1, Harsha Doddapaneni3, Min Wang3, Yiming Zhu3, Huyen Dinh3, Takuya Okusaka11, Norihiro Kokudo12, Tomoo Kosuge7, Tadatoshi Takayama8, Masashi Fukayama10, Richard A. Gibbs3, David A. Wheeler3, Hiroyuki Aburatani2, Tatsuhiro Shibata1, 13
1) Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
2) Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904, Japan.
3) Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
4) Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
5) Department of Molecular Virology & Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
6) Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
7) Hepatoboliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
8) Department of Digestive Surgery, Nihon University School of Medicine, 30-1 Oyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.
9) Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
10) Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
11) Hepatoboliary and Pancreatic Oncology Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
12) Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
13) Laboratory of Molecular Medicine, Human Genome Center, The institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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.
