Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

被引：598

作者：

Totoki, Yasushi ^{[1
]}

Tatsuno, Kenji ^{[2
]}

Covington, Kyle R. ^{[3
]}

Ueda, Hiroki ^{[2
]}

Creighton, Chad J. ^{[3
,4
]}

Kato, Mamoru ^{[1
]}

Tsuji, Shingo ^{[2
]}

Donehower, Lawrence A. ^{[5
]}

Slagle, Betty L. ^{[5
]}

Nakamura, Hiromi ^{[1
]}

Yamamoto, Shogo ^{[2
]}

Shinbrot, Eve ^{[3
]}

Hama, Natsuko ^{[1
]}

Lehmkuhl, Megan ^{[3
]}

Hosoda, Fumie ^{[1
]}

Arai, Yasuhito ^{[1
]}

Walker, Kim ^{[3
]}

Dahdouli, Mahmoud ^{[3
]}

Gotoh, Kengo ^{[2
]}

Nagae, Genta ^{[2
]}

Gingras, Marie-Claude ^{[3
]}

Muzny, Donna M. ^{[3
]}

Ojima, Hidenori ^{[6
]}

Shimada, Kazuaki ^{[7
]}

Midorikawa, Yutaka ^{[8
]}

Goss, John A. ^{[9
]}

Cotton, Ronald ^{[9
]}

Hayashi, Akimasa ^{[2
,10
]}

Shibahara, Junji ^{[10
]}

Ishikawa, Shumpei ^{[10
]}

Guiteau, Jacfranz ^{[9
]}

Tanaka, Mariko ^{[10
]}

Urushidate, Tomoko ^{[1
]}

Ohashi, Shoko ^{[1
]}

Okada, Naoko ^{[1
]}

Doddapaneni, Harsha ^{[3
]}

Wang, Min ^{[3
]}

Zhu, Yiming ^{[3
]}

Huyen Dinh ^{[3
]}

Okusaka, Takuji ^{[11
]}

Kokudo, Norihiro ^{[12
]}

Kosuge, Tomoo ^{[7
]}

Takayama, Tadatoshi ^{[8
]}

Fukayama, Masashi ^{[10
]}

Gibbs, Richard A. ^{[3
]}

Wheeler, David A. ^{[3
]}

Aburatani, Hiroyuki ^{[2
]}

Shibata, Tatsuhiro ^{[1
,13
]}

机构：

[1] Natl Canc Ctr, Res Inst, Div Canc Genom, Tokyo 104, Japan

[2] Univ Tokyo, Adv Sci & Technol Res Ctr, Genome Sci Div, Tokyo 113, Japan

[3] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA

[6] Natl Canc Ctr, Res Inst, Div Mol Pathol, Tokyo 104, Japan

[7] Natl Canc Ctr, Hepatobiliary & Pancreat Surg Div, Tokyo, Japan

[8] Nihon Univ, Sch Med, Dept Digest Surg, Tokyo, Japan

[9] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA

[10] Univ Tokyo, Grad Sch Med, Dept Pathol, Tokyo, Japan

[11] Natl Canc Ctr, Hepatobiliary & Pancreat Oncol Div, Tokyo, Japan

[12] Univ Tokyo, Grad Sch Med, Dept Surg, Hepatobiliary Pancreat Surg Div, Tokyo, Japan

[13] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan

来源：

NATURE GENETICS | 2014年 / 46卷 / 12期

关键词：

SOMATIC MUTATIONS; SUSCEPTIBILITY LOCUS; RECURRENT MUTATIONS; ACTIVATOR PROTEIN; WIDE ASSOCIATION; CANCER; TELOMERASE; SIGNATURES; SRCAP; RECEPTOR;

D O I：

10.1038/ng.3126

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1267 / 1273

页数：7

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