title: IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis.
abstract: BACKGROUND
  Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia. Heterozygous missense mutations in IDH1 at position R132 and in IDH2 at positions R140 and R172 have recently been reported in acute myeloid leukemia. However, little is known about the incidence and prognostic impact of IDH1 and IDH2 mutations in myelodysplastic syndromes.
  
  
  METHODS
  We examined 193 patients with myelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 (R132), IDH2 (R172 and R140), and NPM1 by direct sequencing.
  
  
  RESULTS
  We found that mutations in IDH1 occurred with a frequency of 3.6% in myelodysplastic syndromes (7 mutations in 193 patients) and 7.5% in acute myeloid leukemia following myelodysplastic syndromes (4 mutations in 53 patients). Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following myelodysplastic syndromes (7.5%). No IDH2 R140 or R172 mutations were identified in patients with myelodysplastic syndromes. The presence of IDH1 mutations was associated with a shorter overall survival (HR 3.20; 95% CI 1.47-6.99) and a higher rate of transformation into acute myeloid leukemia (67% versus 28%, P=0.04). In multivariate analysis when considering karyotype, transfusion dependence and International Prognostic Scoring System score, IDH1 mutations remained an independent prognostic marker in myelodysplastic syndromes (HR 3.57; 95% CI 1.59-8.02; P=0.002).
  
  
  CONCLUSIONS
  These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes, and may become useful as a poor risk marker in these patients. These findings await validation in prospective trials.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, Hannover, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.forename: Eva M
authors.initials: EM
authors.lastname: Weissinger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Martin
authors.initials: M
authors.lastname: Wichmann
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Christiane
authors.initials: C
authors.lastname: Schumann
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
mesh_terms: D015415:Biomarkers; D004252:DNA Mutational Analysis; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis
chemical_list: D015415:Biomarkers; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human