Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): A report from the Children's Oncology Group

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Blood (Impact Factor: 10.45). 04/2010; 116(5):702-10. DOI: 10.1182/blood-2010-02-268953
Source: PubMed


Recent studies of WT1 mutations in acute myeloid leukemia (AML) mostly report an association with unfavorable clinical outcome. We screened 842 patients treated on 3 consecutive pediatric AML trials for WT1 zinc-finger mutations. Eighty-five mutations were detected in 70 of 842 patients (8.3%). Mutations occurred predominantly in exon 7 (n = 74) but were also found in exons 8 (n = 5) and 9 (n = 6). Normal karyotype was observed in 35.3% of WT1(mut) patients, whereas 27.5% WT1(mut) patients harbored favorable risk cytogenetics. Patients with or without mutations had similar rates of complete remission after one course of induction chemotherapy. Overall survival (OS) for patients with WT1 mutations was 41% versus 54% for those without mutations (P = .016). Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (28% vs 42%; P = .01). However, FLT3/ITD was present in 36% of the WT1(mut) cohort; WT1(mut) patients without FLT3/ITD had similar OS (56% vs 56%, respectively; P = .8) and EFS (35% and 44%, respectively; P = .34) to patients who were wild type for both mutations. In current risk stratification schemes incorporating cytogenetics and FLT3/ITD status, the presence of WT1 mutations has no independent prognostic significance in predicting outcome in pediatric AML. The clinical trials are registered at as #NCT00002798 and #NCT00070174.

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Available from: Robert B Gerbing, Dec 19, 2014
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    • "The prognostic implications of abnormalities of the Wilms tumour 1 (WT1) gene are not clear in either adults or children with AML (Hollink et al, 2009b; Ho et al, 2010, 2011a; Marcucci et al, 2011). Although the results of one study suggested that WT1 mutations, which occur in about 10% of childhood AML cases, confer a poor prognosis (Hollink et al, 2009b), other studies demonstrated that these mutations have no independent effect on outcome when FLT3 status is taken into account (Ho et al, 2010; Staffas et al, 2011). "
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    ABSTRACT: Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation.
    Preview · Article · Sep 2012 · British Journal of Haematology
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    • "We have arbitrarily included the WT1 mutations as type I aberrations, however, their role in AML still has to be elucidated. (Hollink, et al 2009a, Yang, et al 2007) Moreover, they are not mutually exclusive with some other typical type I aberrations, as shown in the graph. "

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    • "Therefore, additional recurrent aberrations may have a prognostic impact.2 It has been showed that Pediatric AML patients may harbor more than one mutation at diagnosis, some of which with a possible prognostic impact.3–7 Mutations in the NRAS gene are one of these genetic aberrations that play a role in myeloid neoplasia.8 "
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    ABSTRACT: NRAS mutations are the most commonly detected molecular abnormalities in hematologic malignancies, especially in those of myeloid origin. We aimed to determine the frequency of NRAS (NRAS(mutant)) mutation; and its prognostic significance in Egyptian children with acute myelogenous leukemia (AML). Peripheral blood and bone marrow (BM) samples were taken from 39 de novo pediatric AML patients. Twenty subjects with matched age and sex were selected as a control group. Samples from patients and control were analyzed for Exons 1, 2 of NRAS gene using genomic PCR-SSCP method. NRAS mutations at the time of diagnosis was found in 6/39 (15.4%) AML cases. Patients with NRAS(mutant) had no significant improved clinical outcome than patients without mutation. Patients with NRAS(mutant) had similar complete remission (CR) rates compared with non-mutated patients (66.7% vs. 69.5%, P=0.43). Those in CR had a similar relapse rate regardless of the presence of NRAS(mutant) (RR 33.4% vs. 30.2%, P=0.26). However, an adverse prognosis for 3 year overall survival (OS) was associated with the presence of NRAS mutations. This adverse prognosis associated with NRAS mutations was also observed in terms of disease-free survival (DFS) (P=0.007). Univariate analysis showed that unfavorable prognostic factors for DFS were cytogenetic data (P = 0.005) and the NRAS gene mutation (P = 0.002). NRAS(mutant) did not contribute to increase the disease recurrence, however NRAS(mutant) was found to be a poor prognostic factor for children with AML. Further studies to confirm these findings are required because of the small number of patients with NRAS mutation.
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