High-resolution characterization of a hepatocellular carcinoma genome

被引：221

作者：

Totoki, Yasushi ^{[1
]}

Tatsuno, Kenji ^{[2
]}

Yamamoto, Shogo ^{[2
]}

Arai, Yasuhito ^{[1
]}

Hosoda, Fumie ^{[1
]}

Ishikawa, Shumpei ^{[3
]}

Tsutsumi, Shuichi ^{[2
]}

Sonoda, Kohtaro ^{[2
]}

Totsuka, Hirohiko ^{[4
]}

Shirakihara, Takuya ^{[1
]}

Sakamoto, Hiromi ^{[4
]}

Wang, Linghua ^{[2
]}

Ojima, Hidenori ^{[5
]}

Shimada, Kazuaki ^{[6
]}

Kosuge, Tomoo ^{[6
]}

Okusaka, Takuji ^{[7
]}

Kato, Kazuto ^{[8
]}

Kusuda, Jun ^{[9
]}

Yoshida, Teruhiko ^{[4
]}

Aburatani, Hiroyuki ^{[2
]}

Shibata, Tatsuhiro ^{[1
]}

机构：

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

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

[3] Univ Tokyo, Dept Pathol, Grad Sch Med, Bunkyo Ku, Tokyo, Japan

[4] Natl Canc Ctr, Res Inst, Div Genet, Chuo Ku, Tokyo 104, Japan

[5] Natl Canc Ctr, Res Inst, Div Mol Pathol, Chuo Ku, Tokyo 104, Japan

[6] Natl Canc Ctr, Hepatobiliary & Pancreat Surg Div, Chuo Ku, Tokyo, Japan

[7] Natl Canc Ctr, Hepatobiliary & Pancreat Oncol Div, Chuo Ku, Tokyo, Japan

[8] Kyoto Univ, Inst Res Humanities, Grad Sch Biostudies, Inst Integrated Cell Mat Sci, Kyoto, Japan

[9] Natl Inst Biomed Innovat, Osaka, Japan

来源：

NATURE GENETICS | 2011年 / 43卷 / 05期

关键词：

TRANSCRIPTION FACTOR; MUTATIONS; BREAST; MTOR;

D O I：

10.1038/ng.804

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide(1). By massively parallel sequencing(2) of a primary hepatitis C virus-positive hepatocellular carcinoma (36x coverage) and matched lymphocytes (> 28x coverage) from the same individual, we identified more than 11,000 somatic substitutions of the tumor genome that showed predominance of T > C/A > G transition and a decrease of the T > C substitution on the transcribed strand, suggesting preferential DNA repair. Gene annotation enrichment analysis(3) of 63 validated non-synonymous substitutions revealed enrichment of phosphoproteins. We further validated 22 chromosomal rearrangements, generating four fusion transcripts that had altered transcriptional regulation (BCORL1-ELF4) or promoter activity. Whole-exome sequencing(4,5) at a higher sequence depth (> 76x coverage) revealed a TSC1 nonsense substitution in a subpopulation of the tumor cells. This first high-resolution characterization of a virus-associated cancer genome identified previously uncharacterized mutation patterns, intra-chromosomal rearrangements and fusion genes, as well as genetic heterogeneity within the tumor.

引用

页码：464 / +

页数：8

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