Document Detail


CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication.
MedLine Citation:
PMID:  12468438     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The etiology of acute myeloid leukemia (AML) is largely unknown. Biologic and epidemiologic data implicate exogenous toxicants, including cytotoxic drugs, benzene, radiation, and cigarette smoking. Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML. We assayed NRAS oncogene mutation and FLT3 internal tandem duplication in 447 AML patients with an abnormal karyotype treated in Medical Research Council (MRC) AML clinical trials. Functional allelic variant frequencies in genes encoding carcinogen-metabolizing enzymes GSTT1, GSTM1, CYP1A1, CYP2D6, CYP2C19, SULT1A1, and NQO1 were previously determined for this cohort. FLT3 internal tandem duplication (ITD) frequency was 17%, and NRAS mutation 12% for the entire cohort. The 2 mutations were found together in only 4 patients. No association was found between enzyme allelic variant frequencies and the presence of FLT3 ITD for the entire cohort or within cytogenetic subgroups. CYP1A1*2B (Val) high-inducibility variant allele was overrepresented in patients with NRAS mutation compared with no mutation, for (1) the entire AML cohort (n = 8/53 vs 26/371; odds ratio [OR] = 2.36; 95% confidence interval [CI] 1.01-5.53) and (2) the poor-risk karyotype group (n = 6/14 vs 4/89; OR = 15.94; 95% CI 3.71-68.52) comprising patients with partial/complete deletion of chromosome 5 or 7, or abnormalities of chromosome 3. The CYP1A1*2B allele may predispose to the development of these subgroups of AML by augmented phase 1 metabolism to highly reactive intermediates of CYP1A1 substrates, including polycyclic aromatic hydrocarbons, or by generation of oxidative stress as a metabolic by-product.
Authors:
David T Bowen; Marion E Frew; Sara Rollinson; Philippa L Roddam; Ann Dring; Martyn T Smith; Stephen E Langabeer; Gareth J Morgan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-12-05
Journal Detail:
Title:  Blood     Volume:  101     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-03-18     Completed Date:  2003-05-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2770-4     Citation Subset:  AIM; IM    
Affiliation:
Department of Molecular and Cellular Pathology, University of Dundee, Dundee, United Kingdom. d.t.bowen@dundee.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Acute Disease
Adolescent
Adult
Aged
Alleles
Cytochrome P-450 CYP1A1 / genetics*
Gene Frequency
Humans
Karyotyping
Leukemia, Myeloid / genetics*
Middle Aged
Mutation
Prognosis
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins p21(ras) / genetics*
Receptor Protein-Tyrosine Kinases / genetics
Tandem Repeat Sequences
fms-Like Tyrosine Kinase 3
Chemical
Reg. No./Substance:
0/Proto-Oncogene Proteins; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 2.7.10.1/FLT3 protein, human; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.10.1/fms-Like Tyrosine Kinase 3; EC 3.6.5.2/HRAS protein, human; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras)

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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