Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer

Akihiro Fujimoto, Mayuko Furuta, Yasushi Totoki, Tatsuhiko Tsunoda, Mamoru Kato, Yuichi Shiraishi, Hiroko Tanaka, Hiroaki Taniguchi, Yoshiiku Kawakami, Masaki Ueno, Kunihito Gotoh, Shun Ichi Ariizumi, Christopher P. Wardell, Shinya Hayami, Toru Nakamura, Hiroshi Aikata, Koji Arihiro, Keith A. Boroevich, Tetsuo Abe, Kaoru Nakano & 31 others Kazuhiro Maejima, Aya Sasaki-Oku, Ayako Ohsawa, Tetsuo Shibuya, Hiromi Nakamura, Natsuko Hama, Fumie Hosoda, Yasuhito Arai, Shoko Ohashi, Tomoko Urushidate, Genta Nagae, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno, Hidenori Ojima, Nobuyoshi Hiraoka, Takuji Okusaka, Michiaki Kubo, Shigeru Marubashi, Terumasa Yamada, Satoshi Hirano, Masakazu Yamamoto, Hideki Ohdan, Kazuaki Shimada, Osamu Ishikawa, Hiroki Yamaue, Kazuki Chayama, Satoru Miyano, Hiroyuki Aburatani, Tatsuhiro Shibata, Hidewaki Nakagawa

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

Original languageEnglish
Pages (from-to)500-509
Number of pages10
JournalNature Genetics
Volume48
Issue number5
DOIs
Publication statusPublished - 01-05-2016

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Liver Neoplasms
Genome
Mutation
Long Noncoding RNA
Virus Integration
Satellite Viruses
Nucleic Acid Regulatory Sequences
Neoplasm Genes
Virus Diseases
Point Mutation
Carcinogenesis
Binding Sites
Liver
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Fujimoto, A., Furuta, M., Totoki, Y., Tsunoda, T., Kato, M., Shiraishi, Y., ... Nakagawa, H. (2016). Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nature Genetics, 48(5), 500-509. https://doi.org/10.1038/ng.3547
Fujimoto, Akihiro ; Furuta, Mayuko ; Totoki, Yasushi ; Tsunoda, Tatsuhiko ; Kato, Mamoru ; Shiraishi, Yuichi ; Tanaka, Hiroko ; Taniguchi, Hiroaki ; Kawakami, Yoshiiku ; Ueno, Masaki ; Gotoh, Kunihito ; Ariizumi, Shun Ichi ; Wardell, Christopher P. ; Hayami, Shinya ; Nakamura, Toru ; Aikata, Hiroshi ; Arihiro, Koji ; Boroevich, Keith A. ; Abe, Tetsuo ; Nakano, Kaoru ; Maejima, Kazuhiro ; Sasaki-Oku, Aya ; Ohsawa, Ayako ; Shibuya, Tetsuo ; Nakamura, Hiromi ; Hama, Natsuko ; Hosoda, Fumie ; Arai, Yasuhito ; Ohashi, Shoko ; Urushidate, Tomoko ; Nagae, Genta ; Yamamoto, Shogo ; Ueda, Hiroki ; Tatsuno, Kenji ; Ojima, Hidenori ; Hiraoka, Nobuyoshi ; Okusaka, Takuji ; Kubo, Michiaki ; Marubashi, Shigeru ; Yamada, Terumasa ; Hirano, Satoshi ; Yamamoto, Masakazu ; Ohdan, Hideki ; Shimada, Kazuaki ; Ishikawa, Osamu ; Yamaue, Hiroki ; Chayama, Kazuki ; Miyano, Satoru ; Aburatani, Hiroyuki ; Shibata, Tatsuhiro ; Nakagawa, Hidewaki. / Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. In: Nature Genetics. 2016 ; Vol. 48, No. 5. pp. 500-509.
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Fujimoto, A, Furuta, M, Totoki, Y, Tsunoda, T, Kato, M, Shiraishi, Y, Tanaka, H, Taniguchi, H, Kawakami, Y, Ueno, M, Gotoh, K, Ariizumi, SI, Wardell, CP, Hayami, S, Nakamura, T, Aikata, H, Arihiro, K, Boroevich, KA, Abe, T, Nakano, K, Maejima, K, Sasaki-Oku, A, Ohsawa, A, Shibuya, T, Nakamura, H, Hama, N, Hosoda, F, Arai, Y, Ohashi, S, Urushidate, T, Nagae, G, Yamamoto, S, Ueda, H, Tatsuno, K, Ojima, H, Hiraoka, N, Okusaka, T, Kubo, M, Marubashi, S, Yamada, T, Hirano, S, Yamamoto, M, Ohdan, H, Shimada, K, Ishikawa, O, Yamaue, H, Chayama, K, Miyano, S, Aburatani, H, Shibata, T & Nakagawa, H 2016, 'Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer', Nature Genetics, vol. 48, no. 5, pp. 500-509. https://doi.org/10.1038/ng.3547

Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. / Fujimoto, Akihiro; Furuta, Mayuko; Totoki, Yasushi; Tsunoda, Tatsuhiko; Kato, Mamoru; Shiraishi, Yuichi; Tanaka, Hiroko; Taniguchi, Hiroaki; Kawakami, Yoshiiku; Ueno, Masaki; Gotoh, Kunihito; Ariizumi, Shun Ichi; Wardell, Christopher P.; Hayami, Shinya; Nakamura, Toru; Aikata, Hiroshi; Arihiro, Koji; Boroevich, Keith A.; Abe, Tetsuo; Nakano, Kaoru; Maejima, Kazuhiro; Sasaki-Oku, Aya; Ohsawa, Ayako; Shibuya, Tetsuo; Nakamura, Hiromi; Hama, Natsuko; Hosoda, Fumie; Arai, Yasuhito; Ohashi, Shoko; Urushidate, Tomoko; Nagae, Genta; Yamamoto, Shogo; Ueda, Hiroki; Tatsuno, Kenji; Ojima, Hidenori; Hiraoka, Nobuyoshi; Okusaka, Takuji; Kubo, Michiaki; Marubashi, Shigeru; Yamada, Terumasa; Hirano, Satoshi; Yamamoto, Masakazu; Ohdan, Hideki; Shimada, Kazuaki; Ishikawa, Osamu; Yamaue, Hiroki; Chayama, Kazuki; Miyano, Satoru; Aburatani, Hiroyuki; Shibata, Tatsuhiro; Nakagawa, Hidewaki.

In: Nature Genetics, Vol. 48, No. 5, 01.05.2016, p. 500-509.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer

AU - Fujimoto, Akihiro

AU - Furuta, Mayuko

AU - Totoki, Yasushi

AU - Tsunoda, Tatsuhiko

AU - Kato, Mamoru

AU - Shiraishi, Yuichi

AU - Tanaka, Hiroko

AU - Taniguchi, Hiroaki

AU - Kawakami, Yoshiiku

AU - Ueno, Masaki

AU - Gotoh, Kunihito

AU - Ariizumi, Shun Ichi

AU - Wardell, Christopher P.

AU - Hayami, Shinya

AU - Nakamura, Toru

AU - Aikata, Hiroshi

AU - Arihiro, Koji

AU - Boroevich, Keith A.

AU - Abe, Tetsuo

AU - Nakano, Kaoru

AU - Maejima, Kazuhiro

AU - Sasaki-Oku, Aya

AU - Ohsawa, Ayako

AU - Shibuya, Tetsuo

AU - Nakamura, Hiromi

AU - Hama, Natsuko

AU - Hosoda, Fumie

AU - Arai, Yasuhito

AU - Ohashi, Shoko

AU - Urushidate, Tomoko

AU - Nagae, Genta

AU - Yamamoto, Shogo

AU - Ueda, Hiroki

AU - Tatsuno, Kenji

AU - Ojima, Hidenori

AU - Hiraoka, Nobuyoshi

AU - Okusaka, Takuji

AU - Kubo, Michiaki

AU - Marubashi, Shigeru

AU - Yamada, Terumasa

AU - Hirano, Satoshi

AU - Yamamoto, Masakazu

AU - Ohdan, Hideki

AU - Shimada, Kazuaki

AU - Ishikawa, Osamu

AU - Yamaue, Hiroki

AU - Chayama, Kazuki

AU - Miyano, Satoru

AU - Aburatani, Hiroyuki

AU - Shibata, Tatsuhiro

AU - Nakagawa, Hidewaki

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

AB - Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

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