Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

被引：711

作者：

Fujimoto, Akihiro ^{[1
]}

Totoki, Yasushi ^{[2
]}

Abe, Tetsuo ^{[1
]}

Boroevich, Keith A. ^{[1
]}

Hosoda, Fumie ^{[2
]}

Nguyen, Ha Hai ^{[1
]}

Aoki, Masayuki ^{[1
]}

Hosono, Naoya ^{[1
]}

Kubo, Michiaki ^{[1
]}

Miya, Fuyuki ^{[1
]}

Arai, Yasuhito ^{[2
]}

Takahashi, Hiroyuki ^{[2
]}

Shirakihara, Takuya ^{[2
]}

Nagasaki, Masao ^{[3
]}

Shibuya, Tetsuo ^{[3
]}

Nakano, Kaoru ^{[1
]}

Watanabe-Makino, Kumiko ^{[1
]}

Tanaka, Hiroko ^{[3
]}

Nakamura, Hiromi ^{[2
]}

Kusuda, Jun ^{[4
]}

Ojima, Hidenori ^{[5
]}

Shimada, Kazuaki ^{[6
]}

Okusaka, Takuji ^{[7
]}

Ueno, Masaki ^{[8
]}

Shigekawa, Yoshinobu ^{[8
]}

Kawakami, Yoshiiku ^{[9
]}

Arihiro, Koji ^{[10
]}

Ohdan, Hideki ^{[11
]}

Gotoh, Kunihito ^{[12
]}

Ishikawa, Osamu ^{[12
]}

Ariizumi, Shun-ichi ^{[13
]}

Yamamoto, Masakazu ^{[13
]}

Yamada, Terumasa ^{[12
]}

Chayama, Kazuaki ^{[1
,9
]}

Kosuge, Tomoo ^{[6
]}

Yamaue, Hiroki ^{[8
]}

Kamatani, Naoyuki ^{[1
]}

Miyano, Satoru ^{[3
]}

Nakagama, Hitoshi ^{[5
,14
]}

Nakamura, Yusuke ^{[1
,15
]}

Tsunoda, Tatsuhiko ^{[1
]}

Shibata, Tatsuhiro

Nakagawa, Hidewaki ^{[1
]}

机构：

[1] RIKEN, Ctr Genom Med, Yokohama, Kanagawa, Japan

[2] Natl Canc Ctr, Res Inst, Tokyo 104, Japan

[3] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal, Tokyo, Japan

[4] Natl Inst Biomed Innovat, Ibaraki, Osaka, Japan

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

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

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

[8] Wakayama Med Univ, Dept Surg Gastroenterol, Wakayama, Japan

[9] Hiroshima Univ, Sch Med, Dept Med & Mol Sci, Hiroshima, Japan

[10] Hiroshima Univ, Sch Med, Dept Surg Gastroenterol, Hiroshima, Japan

[11] Hiroshima Univ, Sch Med, Dept Pathol Anat, Hiroshima, Japan

[12] Osaka Med Ctr Canc & Cardiovasc Dis, Dept Surg, Osaka, Japan

[13] Tokyo Womens Med Univ, Dept Surg Gastroenterol, Tokyo, Japan

[14] Natl Canc Ctr, Res Inst, Div Canc Dev Syst, Tokyo 104, Japan

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

来源：

NATURE GENETICS | 2012年 / 44卷 / 07期

关键词：

B VIRUS-DNA; HEPATOCELLULAR-CARCINOMA; NEGATIVE REGULATOR; SOMATIC MUTATIONS; INTEGRATION; ALIGNMENT; COMPLEX; TARGETS;

D O I：

10.1038/ng.2291

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in similar to 50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.

引用

页码：760 / U182

页数：7

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