title: Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia.
abstract: OBJECTIVE
  We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers.
  
  
  METHODS
  WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified.
  
  
  RESULTS
  The minor allele of SNP rs16754 (WT1(AG/GG)) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations.
  
  
  CONCLUSIONS
  WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. damm.frederik@mh-hannover.de
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yun
authors.forename: Anika
authors.initials: A
authors.lastname: Grosshennig
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
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
authors.initials: A
authors.lastname: Raghavachar
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kirchner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
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; D014408:Biomarkers, Tumor / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000235:genetics*; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C497422:KMT2A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D025721:WT1 Proteins; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3