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

Akihiro Fujimoto, Yasushi Totoki, Tetsuo Abe, Keith A. Boroevich, Fumie Hosoda, Ha Hai Nguyen, Masayuki Aoki, Naoya Hosono, Michiaki Kubo, Fuyuki Miya, Yasuhito Arai, Hiroyuki Takahashi, Takuya Shirakihara, Masao Nagasaki, Tetsuo Shibuya, Kaoru Nakano, Kumiko Watanabe-Makino, Hiroko Tanaka, Hiromi Nakamura, Jun KusudaHidenori Ojima, Kazuaki Shimada, Takuji Okusaka, Masaki Ueno, Yoshinobu Shigekawa, Yoshiiku Kawakami, Koji Arihiro, Hideki Ohdan, Kunihito Gotoh, Osamu Ishikawa, Shun Ichi Ariizumi, Masakazu Yamamoto, Terumasa Yamada, Kazuaki Chayama, Tomoo Kosuge, Hiroki Yamaue, Naoyuki Kamatani, Satoru Miyano, Hitoshi Nakagama, Yusuke Nakamura, Tatsuhiko Tsunoda, Tatsuhiro Shibata, Hidewaki Nakagawa

Research output: Contribution to journalArticle

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Abstract

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 ∼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.

Original languageEnglish
Pages (from-to)760-764
Number of pages5
JournalNature Genetics
Volume44
Issue number7
DOIs
Publication statusPublished - 01-07-2012

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Liver Neoplasms
Chromatin
Genome
Mutation
Neoplasms
Hepatitis B virus
Virus Integration
Virus Diseases
Hepacivirus
Hepatocellular Carcinoma
Carcinogenesis
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Fujimoto, Akihiro ; Totoki, Yasushi ; Abe, Tetsuo ; Boroevich, Keith A. ; Hosoda, Fumie ; Nguyen, Ha Hai ; Aoki, Masayuki ; Hosono, Naoya ; Kubo, Michiaki ; Miya, Fuyuki ; Arai, Yasuhito ; Takahashi, Hiroyuki ; Shirakihara, Takuya ; Nagasaki, Masao ; Shibuya, Tetsuo ; Nakano, Kaoru ; Watanabe-Makino, Kumiko ; Tanaka, Hiroko ; Nakamura, Hiromi ; Kusuda, Jun ; Ojima, Hidenori ; Shimada, Kazuaki ; Okusaka, Takuji ; Ueno, Masaki ; Shigekawa, Yoshinobu ; Kawakami, Yoshiiku ; Arihiro, Koji ; Ohdan, Hideki ; Gotoh, Kunihito ; Ishikawa, Osamu ; Ariizumi, Shun Ichi ; Yamamoto, Masakazu ; Yamada, Terumasa ; Chayama, Kazuaki ; Kosuge, Tomoo ; Yamaue, Hiroki ; Kamatani, Naoyuki ; Miyano, Satoru ; Nakagama, Hitoshi ; Nakamura, Yusuke ; Tsunoda, Tatsuhiko ; Shibata, Tatsuhiro ; Nakagawa, Hidewaki. / Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. In: Nature Genetics. 2012 ; Vol. 44, No. 7. pp. 760-764.
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abstract = "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 ∼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.",
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Fujimoto, A, Totoki, Y, Abe, T, Boroevich, KA, Hosoda, F, Nguyen, HH, Aoki, M, Hosono, N, Kubo, M, Miya, F, Arai, Y, Takahashi, H, Shirakihara, T, Nagasaki, M, Shibuya, T, Nakano, K, Watanabe-Makino, K, Tanaka, H, Nakamura, H, Kusuda, J, Ojima, H, Shimada, K, Okusaka, T, Ueno, M, Shigekawa, Y, Kawakami, Y, Arihiro, K, Ohdan, H, Gotoh, K, Ishikawa, O, Ariizumi, SI, Yamamoto, M, Yamada, T, Chayama, K, Kosuge, T, Yamaue, H, Kamatani, N, Miyano, S, Nakagama, H, Nakamura, Y, Tsunoda, T, Shibata, T & Nakagawa, H 2012, 'Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators', Nature Genetics, vol. 44, no. 7, pp. 760-764. https://doi.org/10.1038/ng.2291

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. / Fujimoto, Akihiro; Totoki, Yasushi; Abe, Tetsuo; Boroevich, Keith A.; Hosoda, Fumie; Nguyen, Ha Hai; Aoki, Masayuki; Hosono, Naoya; Kubo, Michiaki; Miya, Fuyuki; Arai, Yasuhito; Takahashi, Hiroyuki; Shirakihara, Takuya; Nagasaki, Masao; Shibuya, Tetsuo; Nakano, Kaoru; Watanabe-Makino, Kumiko; Tanaka, Hiroko; Nakamura, Hiromi; Kusuda, Jun; Ojima, Hidenori; Shimada, Kazuaki; Okusaka, Takuji; Ueno, Masaki; Shigekawa, Yoshinobu; Kawakami, Yoshiiku; Arihiro, Koji; Ohdan, Hideki; Gotoh, Kunihito; Ishikawa, Osamu; Ariizumi, Shun Ichi; Yamamoto, Masakazu; Yamada, Terumasa; Chayama, Kazuaki; Kosuge, Tomoo; Yamaue, Hiroki; Kamatani, Naoyuki; Miyano, Satoru; Nakagama, Hitoshi; Nakamura, Yusuke; Tsunoda, Tatsuhiko; Shibata, Tatsuhiro; Nakagawa, Hidewaki.

In: Nature Genetics, Vol. 44, No. 7, 01.07.2012, p. 760-764.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

AU - Fujimoto, Akihiro

AU - Totoki, Yasushi

AU - Abe, Tetsuo

AU - Boroevich, Keith A.

AU - Hosoda, Fumie

AU - Nguyen, Ha Hai

AU - Aoki, Masayuki

AU - Hosono, Naoya

AU - Kubo, Michiaki

AU - Miya, Fuyuki

AU - Arai, Yasuhito

AU - Takahashi, Hiroyuki

AU - Shirakihara, Takuya

AU - Nagasaki, Masao

AU - Shibuya, Tetsuo

AU - Nakano, Kaoru

AU - Watanabe-Makino, Kumiko

AU - Tanaka, Hiroko

AU - Nakamura, Hiromi

AU - Kusuda, Jun

AU - Ojima, Hidenori

AU - Shimada, Kazuaki

AU - Okusaka, Takuji

AU - Ueno, Masaki

AU - Shigekawa, Yoshinobu

AU - Kawakami, Yoshiiku

AU - Arihiro, Koji

AU - Ohdan, Hideki

AU - Gotoh, Kunihito

AU - Ishikawa, Osamu

AU - Ariizumi, Shun Ichi

AU - Yamamoto, Masakazu

AU - Yamada, Terumasa

AU - Chayama, Kazuaki

AU - Kosuge, Tomoo

AU - Yamaue, Hiroki

AU - Kamatani, Naoyuki

AU - Miyano, Satoru

AU - Nakagama, Hitoshi

AU - Nakamura, Yusuke

AU - Tsunoda, Tatsuhiko

AU - Shibata, Tatsuhiro

AU - Nakagawa, Hidewaki

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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 ∼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.

AB - 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 ∼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.

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