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WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups.

Krauth MT, Alpermann T, Bacher U, Eder C, Dicker F, Ulke M, Kuznia S, Nadarajah N, Kern W, Haferlach C, Haferlach T, Schnittger S.

Leukemia. 2014 Aug 11. doi: 10.1038/leu.2014.243

Abstract

To investigate frequency and prognostic impact of WT1 mutations (mut), we analyzed 3,157 unselected acute myeloid leukemia patients for WT1mut in exons 7 and 9. 188 WT1 mutations were detected (exon 7: n=150, exon 9: n=38). 141 were frameshift, 24 missense, 14 nonsense, 7 splice site and 2 indel mutations. In 175/3,157 (5.5%) patients a WT1mut was found. Higher frequencies were detected in patients with biallelic CEBPAmut (13.6% P=0.001), followed by t(15;17)/PML-RARA (11.0%, P=0.004), and FLT3-ITD (8.5%, P<0.001). WT1mut were rare in DNMT3Amut (4.4%, P=0.014), ASXL1mut (1.7%, P<0.001), IDH2R140 (1.7%, P=0.001), and IDH1R132 (0.9%, P<0.001), and not detected in complex karyotypes (P=0.047). They were more frequent in females than in males (6.6% vs. 4.7%) (P=0.014) and in patients <60 years (P<0.001). Analysis of paired samples of 35 patients revealed a relatively unstable character of WT1mut (65.7% retained, 34.3% lost WT1mut at relapse). In the total cohort and subgroups with high WT1mut incidences (biallelic CEBPAmut, PML-RARA), WT1mut had no impact on prognosis. In normal karyotype AML, WT1mut patients had shorter EFS (10.8 vs. 17.9 m, P=0.008). In multivariate analysis, WT1mut had an independent adverse impact on EFS (P=0.002, HR: 1.64) besides FLT3-ITD status (P<0.001, HR: 1.71) and age (P<0.001, HR: 1.28).Leukemia accepted article preview online, 11 August 2014; doi:10.1038/leu.2014.243.


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