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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
Author(s) -
Ho Phoenix A.,
Alonzo Todd A.,
Gerbing Robert B.,
Kuhn Julia,
Pollard Jessica A.,
Hirsch Betsy,
Raimondi Susana C.,
Gamis Alan S.,
Meshinchi Soheil
Publication year - 2014
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.24700
Subject(s) - snp , quartile , oncology , medicine , single nucleotide polymorphism , genotype , snp array , univariate analysis , multivariate analysis , gene , biology , genetics , confidence interval
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. Procedure 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. Conclusion 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. Pediatr Blood Cancer 2014;61:81–88. © 2013 Wiley Periodicals, Inc.