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

Virappane, P., Gale, R., Hills, Robert Kerrin ORCID: https://orcid.org/0000-0003-0166-0062, Kakkas, I., Summers, K., Stevens, J., Allen, C., Green, C., Quentmeier, H., Drexler, H., Burnett, Alan Kenneth, Linch, D., Bonnet, D., Lister, T. A. and Fitzgibbon, J. 2008. 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. Journal of Clinical Oncology 26 (33) , pp. 5429-5435. 10.1200/JCO.2008.16.0333

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Additional Information:	Presented at the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA.
Publisher:	American Society of Clinical Oncology
ISSN:	0732-183X
Last Modified:	24 Oct 2022 11:56
URI:	https://orca.cardiff.ac.uk/id/eprint/49817

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