Dataset Information

Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.

ABSTRACT: To analyze the prognostic impact of Wilms' tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITD(negative)/NPM1(mutated) as low risk v FLT3-ITD(positive) and/or NPM1(wild-type) as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.

SUBMITTER: Paschka P

PROVIDER: S-EPMC2653131 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.

Paschka Peter P Marcucci Guido G Ruppert Amy S AS Whitman Susan P SP Mrózek Krzysztof K Maharry Kati K Langer Christian C Baldus Claudia D CD Zhao Weiqiang W Powell Bayard L BL Baer Maria R MR Carroll Andrew J AJ Caligiuri Michael A MA Kolitz Jonathan E JE Larson Richard A RA Bloomfield Clara D CD

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20080616 28

<h4>Purpose</h4>To analyze the prognostic impact of Wilms' tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase doma ...[more]

PMID: 18559874

Similar Datasets

Project description:Background and Methods: Acute myeloid leukemia (AML), which starts in the bone marrow, is a group of hematopoietic stem cell disorders. Chloride intracellular channel 4 (CLIC4) is regulated by p53, c-Myc, and TGF-?. It induces the NF-?B-dependent activation of HIF (hypoxia-inducible factor) and participates in tumor growth through its microenvironmental function. However, its prognostic value in AML remains unclear, as well as its co-expression biomarkers. In this study, we evaluated the prognostic significance of CLIC4 expression using two independent large cohorts of cytogenetically normal AML (CN-AML) patients. Multivariable analysis and multi-omics analysis with weighted correlation network analysis (WGCNA) in the CN-AML group were also presented. Based on CLIC4 and its related genes, microRNA-target gene interaction network analysis and downstream gene ontology analysis were performed to unveil the complex functions behind CLIC4. Results: We demonstrated that the overexpression of CLIC4 was notably associated with unfavorable outcome in the two independent cohorts of CN-AML patients [overall survival (OS) and event-free survival (EFS): P < 0.0001, n = 185; OS: P = 0.016, n = 232], as well as in the European LeukemiaNet (ELN) Intermediate-I group (OS: P = 0.015, EFS: P = 0.012, n = 115), the National Comprehensive Cancer Network Intermediate Risk AML group (OS and EFS: P < 0.0001, n = 225), and the non-M3 AML group (OS and EFS: P < 0.0001, n = 435). Multivariable analysis further validated CLIC4 as a high-risk factor in the CN-AML group. Multi-omics analysis presented the overexpression of CLIC4 as associated with the co-expression of the different gene sets in leukemia, up/downregulation of the immune-related pathways, dysregulation of microRNAs, and hypermethylation around the CpG islands, in open sea regions, and in different gene structural fragments including TSS1500, gene body, 5'UTR region, 3'UTR region, and the first exon. By further performing WGCNA on multi-omics data, certain biomarkers that are co-expressed with CLIC4 were also unveiled. Conclusion: We demonstrated that CLIC4 is a novel, potential unfavorable prognosticator and therapeutic target for CN-AML. As having a key role in CN-AML, the interactions between CLIC4 and other genomics and transcriptomics data were confirmed by performing microRNA-target gene interaction network analysis and gene ontology enrichment analysis. The experimental result provides evidence for the clinical strategy selection of CN-AML patients.

Dataset Information

Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.

Publications

Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets