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- Hideki Makishima
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Ryunosuke Saiki
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Yasuhito Nannya
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Sophia Korotev
- 2Departments of Medicine and Human Genetics, Section of Hematology/Oncology, The University of Chicago, Chicago, IL
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- Carmelo Gurnari
- 3Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
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- June Takeda
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Yukihide Momozawa
- 5Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama, Japan
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- Steve Best
- 6King’s College Hospital NHS Foundation Trust, and King’s College London, London, United Kingdom
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- Pramila Krishnamurthy
- 6King’s College Hospital NHS Foundation Trust, and King’s College London, London, United Kingdom
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- Tetsuichi Yoshizato
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Yoshiko Atsuta
- 7Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
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- Yusuke Shiozawa
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Yuka Iijima-Yamashita
- 9Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan
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- Kenichi Yoshida
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Yuichi Shiraishi
- 10National Cancer Center Research Institute, Division of Genome Analysis Platform Development, Tokyo, Japan
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- Yasunobu Nagata
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Nobuyuki Kakiuchi
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Makoto Onizuka
- 11Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan
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- Kenichi Chiba
- 10National Cancer Center Research Institute, Division of Genome Analysis Platform Development, Tokyo, Japan
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- Hiroko Tanaka
- 12Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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- Ayana Kon
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Yotaro Ochi
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Masahiro M. Nakagawa
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Rurika Okuda
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Takuto Mori
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Akinori Yoda
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
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- Hidehiro Itonaga
- 13Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
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- Yasushi Miyazaki
- 13Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
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- Masashi Sanada
- 9Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan
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- Takayuki Ishikawa
- 14Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan
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- Shigeru Chiba
- 15Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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- Hisashi Tsurumi
- 16Department of Hematology, Gifu University, Gifu, Japan
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- Senji Kasahara
- 17Department of Hematology, Gifu Municipal Hospital, Gifu, Japan
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- Carsten Müller-Tidow
- 18Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
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- Akifumi Takaori-Kondo
- 19Department of Hematology, Kyoto University, Kyoto, Japan
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- Kazuma Ohyashiki
- 20Department of Hematology, Tokyo Medical University, Tokyo, Japan
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- Toru Kiguchi
- 21Chugoku Central Hospital, Fukuyama, Japan
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- Fumihiko Matsuda
- 22Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Joop H. Jansen
- 23Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
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- Chantana Polprasert
- 24Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
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- Piers Blombery
- 25Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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- Yoichiro Kamatani
- 26Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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- Satoru Miyano
- 10National Cancer Center Research Institute, Division of Genome Analysis Platform Development, Tokyo, Japan
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- Luca Malcovati
- 28Department of Molecular Medicine, University of Pavia, Pavia, Italy
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- Torsten Haferlach
- 29MLL Munich Leukemia Laboratory, Munich, Germany
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- Michiaki Kubo
- 30Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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- Mario Cazzola
- 28Department of Molecular Medicine, University of Pavia, Pavia, Italy
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- Austin G. Kulasekararaj
- 6King’s College Hospital NHS Foundation Trust, and King’s College London, London, United Kingdom
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- Lucy A. Godley
- 2Departments of Medicine and Human Genetics, Section of Hematology/Oncology, The University of Chicago, Chicago, IL
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- Jaroslaw P. Maciejewski
- 3Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
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- Seishi Ogawa
- 1Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
抄録
<jats:title>Abstract</jats:title><jats:p>Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.</jats:p>
収録刊行物
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- Blood
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Blood 141 (5), 534-549, 2023-02-02
American Society of Hematology
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詳細情報 詳細情報について
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- CRID
- 1360580232387658240
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- ISSN
- 15280020
- 00064971
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- データソース種別
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- Crossref
- KAKEN