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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-01-0228.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2770-2774
NEOPLASIA
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
David T. Bowen,
Marion E. Frew,
Sara Rollinson,
Philippa L. Roddam,
Ann Dring,
Martyn T. Smith,
Stephen E. Langabeer, and
Gareth J. Morgan
From the Department of Molecular and Cellular
Pathology, University of Dundee, Dundee, United Kingdom; Academic Unit
of Hematology and Oncology, University of Leeds, Leeds, United Kingdom;
School of Public Health, University of California, Berkeley, CA;
Department of Hematology, University College London, London,
United Kingdom.
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.
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