Niavarani Ahmadreza, Horswell Stuart, Sadri Ramin, Bonnet Dominique
Ann Hematol. 2016 Jan;95(2):179-90. doi: 10.1007/s00277-015-2534-5.
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.
据报道，肾母细胞瘤1（WT1）第7外显子内的单核苷酸多态性（SNP）rs16754与急性髓系白血病（AML）的预后有关。我们评估了选定的WT1 SNP以及正常核型（NK）-AML中WT1突变的潜在关联，并评估了这些正常基因变异的预后价值。使用TaqMan分析对474例年轻成人NK-AML患者的诊断样本进行基因分型，检测5个WT1 SNP，并对WT1第7和第9外显子进行直接测序。对5个WT1基因变异的分析显示，rs2234593等位基因C与WT1 Ex7突变相关。对相同变异的预后研究发现，rs2234593与复发和总生存期（OS）显著相关。与rs2234593CC的患者相比，rs2234593AA/AC患者的10年总生存率显著更高（50%对36%，风险比（HR）=0.69（0.52-0.90），p=0.006），复发累积发生率（CIR）更低（36%对51%，HR=0.62（0.45-0.86），p=0.004）。在对包括FMS样酪氨酸激酶3内部串联重复（FLT3-ITD）和核磷蛋白1（NPM1）突变在内的基本协变量进行调整后，AA基因型对CIR的影响仍然显著（HR=0.60（0.41-0.89），p=0.009），有一些生存改善的证据（HR=0.75（0.55-1.03），p=0.07）。多变量分析显示，WT1 Ex7突变是主要的复发预测因素，在考虑Ex7突变后，rs2234593-A有影响趋势（p=0.07）。未发现先前报道的rs16754-G有调整后的风险获益。总之，WT1正常基因变异rs2234593与WT1 Ex7的突变状态相关，是NK-AML中独立于FLT3-ITD和NPM1突变的进一步预后标志物。
