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Virappane, Priya; Gale, Rosemary; Hills, Robert; Kakkas, Ioannis; Summers, Karin; Stevens, Jane; Allen, Christopher; Green, Claire; Quentmeier, Hilmar; Drexler, Hans; Burnett, Alan; Linch, David; Bonnet, Dominique; Lister, T. Andrew; Fitzgibbon, Jude

Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party

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  • Media type: E-Article
  • Title: Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party
  • Contributor: Virappane, Priya; Gale, Rosemary; Hills, Robert; Kakkas, Ioannis; Summers, Karin; Stevens, Jane; Allen, Christopher; Green, Claire; Quentmeier, Hilmar; Drexler, Hans; Burnett, Alan; Linch, David; Bonnet, Dominique; Lister, T. Andrew; Fitzgibbon, Jude
  • Published: American Society of Clinical Oncology (ASCO), 2008
  • Published in: Journal of Clinical Oncology, 26 (2008) 33, Seite 5429-5435
  • Language: English
  • DOI: 10.1200/jco.2008.16.0333
  • ISSN: 0732-183X; 1527-7755
  • Origination:
  • Footnote:
  • Description: Purpose To determine the clinical relevance of Wilms’ tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK). Patients and Methods Exons 7 and 9 of WT1 were screened in samples from 470 young adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis. Results Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio [OR] = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio [HR] = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor. Conclusion WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.
  • Access State: Open Access