The Wilms Tumor-1 (WT1) rs2234593 variant is a prognostic factor in normal karyotype acute myeloid leukemia

Abstract

The single-nucleotide polymorphism (SNP) within Wilms tumor-1 (WT1) exon 7, rs16754, has been arguably reported to be implicated in acute myeloid leukemia (AML) prognosis. We assessed the potential association of selected WT1 SNPs as well as WT1 mutations in normal karyotype (NK)-AML and evaluated the prognostic value of these normal gene variants. Diagnostic samples from a series of 474 young adult NK-AML patients were used to genotype five WT1 SNPs using TaqMan assays and to directly sequence WT1 exons 7 and 9. Analysis of five WT1 gene variants showed an association of rs2234593 allele C with WT1 Ex7 mutation. Prognostic study of the same variants identified rs2234593 significantly associated with relapse and overall survival (OS). Patients with rs2234593AA/AC showed significantly higher 10-year OS (50 vs 36 %, hazard ratio (HR) = 0.69 (0.52–0.90), p = 0.006) and lower cumulative incidence of relapse (CIR) (36 vs 51 %, HR = 0.62 (0.45–0.86), p = 0.004) compared to those with rs2234593CC. The effect of AA genotype on CIR remained significant after adjustment for basic covariates including FLT3 internal-tandem duplication (FLT3-ITD) and nucleophosmin 1 (NPM1) mutations (HR = 0.60 (0.41–0.89), p = 0.009), with some evidence of improved survival (HR = 0.75 (0.55–1.03), p = 0.07). A multivariate analysis showed WT1 Ex7-mutant as the major relapse predictor, with a tendency for rs2234593-A effect after allowing for Ex7 mutation (p = 0.07). No adjusted risk benefit was found for previously reported rs16754-G. In conclusion, WT1 normal gene variant rs2234593 is associated with mutational status of WT1 Ex7 and is a further prognostic marker independent from FLT3-ITD and NPM1 mutations in NK-AML.