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Nat Genet. 2014 Dec;46(12):1267-73. doi: 10.1038/ng.3126. Epub 2014 Nov 2.

Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.

Author information

1
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
2
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
4
1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
5
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
6
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
7
Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
8
Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
9
Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
10
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.
11
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
12
Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
13
Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
14
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.

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.

PMID:
25362482
DOI:
10.1038/ng.3126
[Indexed for MEDLINE]

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