title: 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.
abstract: 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.affiliation: Department of Molecular and Cellular Pathology, University of Dundee, Dundee, United Kingdom. d.t.bowen@dundee.ac.uk
authors.forename: David T
authors.initials: DT
authors.lastname: Bowen
authors.forename: Marion E
authors.initials: ME
authors.lastname: Frew
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.forename: Philippa L
authors.initials: PL
authors.lastname: Roddam
authors.forename: Ann
authors.initials: A
authors.lastname: Dring
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Langabeer
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D011518:Proto-Oncogene Proteins; D019363:Cytochrome P-450 CYP1A1; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)