title: WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups.
abstract: To investigate frequency and prognostic impact of Wilms tumor 1 (WT1) mutations (mut), we analyzed 3157 unselected acute myeloid leukemia patients for WT1mut in exons 7 and 9. In total, 188 WT1 mutations were detected (exon 7: n=150, exon 9: n=38); 141 were frameshift, 24 missense, 14 non-sense, 7 splice site and 2 indel mutations. In 175/3157 (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 event-free survival (EFS) (10.8 vs 17.9 m, P=0.008). In multivariate analysis, WT1mut had an independent adverse impact on EFS (P=0.002, hazard ratio (HR): 1.64) besides FLT3-ITD status (P<0.001, HR: 1.71) and age (P<0.001, HR: 1.28).
authors.affiliation: 1] MLL Munich Leukemia Laboratory, Munich, Germany [2] Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.
authors.forename: M-T
authors.initials: MT
authors.lastname: Krauth
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Bacher
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Eder
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Dicker
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ulke
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kuznia
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Nadarajah
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kern
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001369:Axons; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics; D012737:Sex Factors; D016019:Survival Analysis; D025721:WT1 Proteins / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000717967:DNMT3A protein, human; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D025721:WT1 Proteins; C583751:WT1 protein, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
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