title: Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.
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.
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Furuta
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.|Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|CREST, JST, Tokyo, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: CREST, JST, Tokyo, Japan.|Department of Bioinformatics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima, Japan.
authors.forename: Yoshiiku
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Kunihito
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Ariizumi
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.affiliation: Department of Anatomical Pathology, Hiroshima University School of Medicine, Hiroshima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Keith A
authors.identifier: 0000-0001-7095-7332
authors.initials: KA
authors.lastname: Boroevich
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Abe
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maejima
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sasaki-Oku
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Ohsawa
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shibuya
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Urushidate
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tatsuno
authors.affiliation: Department of Pathology, Keio University School of Medicine, Shinjyuku-ku, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
authors.affiliation: Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Marubashi
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirano
authors.affiliation: Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterological Surgery, Hiroshima University School of Medicine, Hiroshima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.affiliation: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaue
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima, Japan.|Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
mesh_terms: D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D040342:Genetic Structures; D015894:Genome, Human; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D011379:Prognosis; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D016662:Virus Integration
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins