title: The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: report from the Children's Oncology Group.
abstract: BACKGROUND
  WT1 is aberrantly over-expressed in most cases of AML. We recently demonstrated that WT1 SNP rs16754 correlates with favorable outcome and high diagnostic WT1 expression in childhood AML. We examined the clinical correlates of diagnostic WT1 expression within a contemporary COG trial and determined whether its prognostic impact differs between SNP+ and SNP- patients.
  
  
  METHODS
  WT1 mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 225 patients enrolled on COG-AAML03P1. Direct sequencing of WT1 exon 7 was performed to determine SNP rs16754 genotype. WT1 expression was correlated with disease characteristics, SNP status, and outcome.
  
  
  RESULTS
  Patients were categorized into four groups (quartiles: Q1 through Q4) based on diagnostic WT1 expression for analysis. FLT3/ITD (P = 0.017) and WT1 mutations (P < 0.001) both occurred more frequently in patients with the highest WT1 expression. SNP rs16754 frequency did not vary significantly among the quartiles. When all patients were considered, survival outcomes were similar between quartiles. However, when only SNP- patients (n = 150) were analyzed, those with highest WT1 expression (Q4) had the poorest OS (51% vs. 72% for Q1-Q3, P = 0.006) and EFS (35% vs. 54% for Q1-Q3, P = 0.031). Among SNP+ patients (n = 75), survival did not vary significantly between WT1 expression quartiles.
  
  
  CONCLUSIONS
  Although WT1 expression was not prognostic when all patients were considered together, stratifying patients by SNP rs16754 genotype revealed significant differences in outcome. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression quartile.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Pediatric Hematology/Oncology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington; Children's Oncology Group, Arcadia, California.
authors: Phoenix A
authors: PA
authors: Ho
authors: Todd A
authors: TA
authors: Alonzo
authors: Robert B
authors: RB
authors: Gerbing
authors: Julia
authors: J
authors: Kuhn
authors: Jessica A
authors: JA
authors: Pollard
authors: Betsy
authors: B
authors: Hirsch
authors: Susana C
authors: SC
authors: Raimondi
authors: Alan S
authors: AS
authors: Gamis
authors: Soheil
authors: S
authors: Meshinchi
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D000079982:Gemtuzumab; D015973:Gene Expression Regulation, Leukemic; D016162:Genes, Wilms Tumor; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000079982:Gemtuzumab
keywords: AML; WT1; molecular diagnosis and therapy; prognostic factors; rs16754