title: Dynamics of clonal evolution in myelodysplastic syndromes.
abstract: To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Meggendorfer
authors.affiliation: Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.identifier: http://orcid.org/0000-0003-3139-9272
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Hirsch
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Teodora
authors.initials: T
authors.lastname: Kuzmanovic
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: LaFramboise
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hosono
authors.affiliation: Laboratory of Sequence 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 Sequence 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: Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
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, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Inés
authors.initials: I
authors.lastname: Gómez-Seguí
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Holleh D
authors.initials: HD
authors.lastname: Husseinzadeh
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Swapna
authors.initials: S
authors.lastname: Thota
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Guinta
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Dienes
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: Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyawaki
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: 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: Division of Hematology-Oncology, Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.affiliation: Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells / Q000378:metabolism; D018450:Disease Progression; D059472:Exome / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D000090243:Nucleophosmin