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 NakanoKazuhiro 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

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268 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 - 2016 May 1

ASJC Scopus subject areas

  • Genetics

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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, S. I., Wardell, C. P., Hayami, S., Nakamura, T., Aikata, H., Arihiro, K., Boroevich, K. A., Abe, T., ... 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