title: Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor.
abstract: OBJECTIVE
  We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers.
  
  
  METHODS
  IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified.
  
  
  RESULTS
  IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3-internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles.
  
  
  CONCLUSIONS
  IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.
authors.affiliation: Department of Hematology, Hannover Medical School, Carl-Neuberg Str 1, 30625 Hannover, Germany. wagner.katharina@mh-hannover.de
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Kerstin
authors.initials: K
authors.lastname: Görlich
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Irina
authors.initials: I
authors.lastname: Schäfer
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Heit
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Günter
authors.initials: G
authors.lastname: Schlimok
authors.forename: Aruna A
authors.initials: AA
authors.lastname: Raghavachar
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Hartmut H
authors.initials: HH
authors.lastname: Kirchner
authors.forename: Wolfram
authors.initials: W
authors.lastname: Brugger
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Gerhard
authors.initials: G
authors.lastname: Heil
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
mesh_terms: D000293:Adolescent; D000328:Adult; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D005858:Germany; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000716967:NPM1 protein, human; D012333:RNA, Messenger; D000090243:Nucleophosmin; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human