title: Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation.
abstract: Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk.TP53and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype,TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better inTP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest thatTP53and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutatedTP53or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.
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: Yasuhito
authors.initials: Y
authors.lastname: Nannya
authors.affiliation: Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Atsuta
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Pediatrics, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Iijima-Yamashita
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: 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: 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: Yasunobu
authors.initials: Y
authors.lastname: Nagata
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: Nobuyuki
authors.initials: N
authors.lastname: Kakiuchi
authors.affiliation: Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Aichi, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
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: 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: Laboratory of Sequence 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: Hiroo
authors.initials: H
authors.lastname: Ueno
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro M
authors.initials: MM
authors.lastname: Nakagawa
authors.affiliation: Department of Translational Hematology and Oncology Research and Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Itonaga
authors.affiliation: Division of Hematology, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kanda
authors.affiliation: Department of Translational Hematology and Oncology Research and Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Translational Hematology and Oncology Research and Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
authors.affiliation: 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.|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: 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 Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002869:Chromosome Aberrations; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D012306:Risk; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins