title: Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms.
abstract: Mutations in isocitrate dehydrogenase 1/2 (IDH1/2(MT)) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower- to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1(MT) and IDH2(MT) are ancestral in up to 14/74 (19%) vs 34/99 (34%; P=0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2(MT) was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1(MT) cases were associated with a worse prognosis than subclonal IDH1(MT) cases, whereas the position of IDH2(MT) within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1(MT) cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2(MT) cases. Our data demonstrate important clinical and biological differences between IDH1(MT) and IDH2(MT) myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2(MT) inhibitors of IDH1/2(MT) patients.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.|Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Molenaar
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Thota
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Clemente
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hirsh
authors.affiliation: Department of Medicine, Human Oncology & Pathogenesis, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Viny
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hosano
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Meibergdreef 15, Amsterdam, The Netherlands.
authors.forename: F E
authors.initials: FE
authors.lastname: Bleeker
authors.affiliation: Munich Leukemia Laboratories, Max-Lebsche-Platz 31, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Meggendorfer
authors.affiliation: Munich Leukemia Laboratories, Max-Lebsche-Platz 31, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
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: K
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: H
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C J F
authors.initials: CJ
authors.lastname: van Noorden
authors.affiliation: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Carraway
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.|Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Munich Leukemia Laboratories, Max-Lebsche-Platz 31, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000368:Aged; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D000090243:Nucleophosmin; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000716967:NPM1 protein, human; D011518:Proto-Oncogene Proteins; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human
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