title: Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.
abstract: BACKGROUND
  The alleles of the Wilms tumor 1 (WT1) polymorphism rs16754 harbor adenine (A) or guanine (G). Recently, rs16754 has been reported to affect the outcome of patients with cytogenetically normal acute myeloid leukemia. To validate this finding, we investigated pretreatment features and outcome associated with rs16754 in a large cohort of patients with cytogenetically normal acute myeloid leukemia.
  
  
  METHODS
  Four-hundred and thirty-three intensively treated and molecularly characterized cytogenetically normal patients with de novo acute myeloid leukemia (18-83 years old) were analyzed for rs16754. To gain biological insights, we studied the gene- and microRNA-expression profiles for associations with rs16754.
  
  
  RESULTS
  Three-hundred and nine (71%) patients were homozygous for A (WT1(AA)), 112 (26%) were heterozygous (WT1(AG)) and 12 (3%) were homozygous for G (WT1(GG)). For comparison with previous studies, we grouped WT1(AG) and WT1(GG) patients and compared them with WT1(AA) patients divided into younger (<60 years) and older (≥60 years) adults. We found no independent prognostic impact of WT1(AA). However, WT1(GG) patients, who were less often Caucasian than WT1(AG) (P=0.001) or WT1(AA) (P=0.008) patients, and had TET2 mutations more often than WT1(AG) (P=0.02) patients, had, among patients with FLT3-internal tandem duplication and/or NPM1 wild-type, better disease-free (P=0.02) and overall survival (P=0.04) than WT1(AA) and WT1(AG) patients combined. Unsupervised and supervised analyses of the gene- and microRNA-expression profiles suggested that there were no distinct expression patterns associated with any rs16754 genotype.
  
  
  CONCLUSIONS
  We did not observe the previously reported adverse impact of WT1(AA) but found favorable outcomes associated with the homozygous WT1(GG). Considering its low frequency, confirmatory studies are necessary. The biological significance of rs16754 remains questionable as no distinct expression profiles were associated with the genotypes.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D025721:WT1 Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D035683:MicroRNAs; C000716967:NPM1 protein, human; D025721:WT1 Proteins; D000090243:Nucleophosmin