Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

Yasushi Totoki, Kenji Tatsuno, Kyle R. Covington, Hiroki Ueda, Chad J. Creighton, Mamoru Kato, Shingo Tsuji, Lawrence A. Donehower, Betty L. Slagle, Hiromi Nakamura, Shogo Yamamoto, Eve Shinbrot, Natsuko Hama, Megan Lehmkuhl, Fumie Hosoda, Yasuhito Arai, Kim Walker, Mahmoud Dahdouli, Kengo Gotoh, Genta NagaeMarie Claude Gingras, Donna M. Muzny, Hidenori Ojima, Kazuaki Shimada, Yutaka Midorikawa, John A. Goss, Ronald Cotton, Akimasa Hayashi, Junji Shibahara, Shumpei Ishikawa, Jacfranz Guiteau, Mariko Tanaka, Tomoko Urushidate, Shoko Ohashi, Naoko Okada, Harsha Doddapaneni, Min Wang, Yiming Zhu, Huyen Dinh, Takuji Okusaka, Norihiro Kokudo, Tomoo Kosuge, Tadatoshi Takayama, Masashi Fukayama, Richard A. Gibbs, David A. Wheeler, Hiroyuki Aburatani, Tatsuhiro Shibata

Research output: Contribution to journalArticle

333 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1267-1273
Number of pages7
JournalNature genetics
Volume46
Issue number12
DOIs
Publication statusPublished - 2014 Dec 11

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Trans-ancestry mutational landscape of hepatocellular carcinoma genomes'. Together they form a unique fingerprint.

  • Cite this

    Totoki, Y., Tatsuno, K., Covington, K. R., Ueda, H., Creighton, C. J., Kato, M., Tsuji, S., Donehower, L. A., Slagle, B. L., Nakamura, H., Yamamoto, S., Shinbrot, E., Hama, N., Lehmkuhl, M., Hosoda, F., Arai, Y., Walker, K., Dahdouli, M., Gotoh, K., ... Shibata, T. (2014). Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nature genetics, 46(12), 1267-1273. https://doi.org/10.1038/ng.3126