title: Integrated molecular analysis of adult T cell leukemia/lymphoma.
abstract: Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kitanaka
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: Division of Systems Biology, Center for Neurological Disease and Cancer, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Jun-Ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
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: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryohei
authors.identifier: http://orcid.org/0000-0003-2486-1393
authors.initials: R
authors.lastname: Ishii
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Muto
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kotani
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yosaku
authors.initials: Y
authors.lastname: Watatani
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: June
authors.initials: J
authors.lastname: Takeda
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
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: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Frontier Life Science, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Iwanaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Guangyong
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Kisato
authors.initials: K
authors.lastname: Nosaka
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Hishizawa
authors.affiliation: Department of Hematology, Sasebo City General Hospital, Sasebo, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Itonaga
authors.affiliation: Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Imaizumi
authors.affiliation: Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Munakata
authors.affiliation: KAN Research Institute, Inc., Kobe, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogasawara
authors.affiliation: KAN Research Institute, Inc., Kobe, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Sato
authors.affiliation: KAN Research Institute, Inc., Kobe, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sasai
authors.affiliation: KAN Research Institute, Inc., Kobe, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Muramoto
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Penova
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shide
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kubuki
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hidaka
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kameda
authors.affiliation: Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakamaki
authors.affiliation: Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishiyama
authors.affiliation: Division of Hematology, Department of Internal Medicine, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyawaki
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kensei
authors.identifier: http://orcid.org/0000-0002-7859-3227
authors.initials: K
authors.lastname: Tobinai
authors.affiliation: Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Akifumi
authors.identifier: http://orcid.org/0000-0001-7678-4284
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
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: Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.|Laboratory of Molecular Medicine, Human Genome Center, The institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Masao
authors.identifier: http://orcid.org/0000-0002-0473-754X
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Laboratory of DNA Information 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: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Kazuya
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authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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authors.initials: S
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mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D059472:Exome / Q000235:genetics*; D016356:Gene Products, tax / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D059467:Transcriptome / Q000235:genetics*
chemical_list: D016356:Gene Products, tax; C514970:tax protein, Human T-lymphotrophic virus 1