The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia

Abstract

Background and ObjectivesWe examined common polymorphisms in the genes for glutathione S-transferase (GST), cytochrome P450 (CYP), quinone oxoreductase (NQO1), methylene tetrahydrofolate reductase (MTHFR), and thymidylate synthetase (TYMS) and the role of gender associated with the susceptibility to de novo acute leukemia (AL). Design and MethodsWe conducted a case-control study analyzing the prevalence of the polymorphisms CYP1A1*2A, CYP2E1*5B, CYP3A4*1B, del{GSTT1}, del{GSTM1}, NQO1*2, MTHFR C6777, and TYMS 2R/3R in 443 patients with AL [302 with acute myeloblastic leukemia (AML) and 141 with acute lymphoblastic leukemia (ALL)] and 454 control volunteers, using polymerase chain reaction (PCR)-based methods. ResultsWe found a higher incidence of del{GSTT1} in patients with AML than among controls (25.6% vs. 13.7%, OR=2.2, p<0.001) and a higher incidence of NQO1*2 homozygosity (NQO1*2hom.) in males with the M3 FAB subtype than in control males (8.6% vs. 2.2%, OR=4.9, p=0.02). The del{GSTT1} and NQO1*2hom. polymorphisms increased the risk of ALL (OR=2.2 and 3.0, p=0.001 and 0.003, respectively). The higher risk conferred by NQO1*2hom. and del{GSTT1} mainly affected males (OR=6.1 and 2.4; p=0.002 and 0.005, respectively). Interpretation and ConclusionsMales harboring NQO1*2hom. and del{GSTT1} polymorphisms showed a higher risk than females of developing AL. Thus, gender might influence the risk of AL associated with these genetic polymorphisms. On the whole AL is more common in males of all age groups, 4 a fact that remains unexplained. Although the clinical and biological aspects of leukemia are well documented, little is known about the factors that condition an individual's susceptibility to de novo leukemia. Normal polymorphic variations in several genes, together with dietary effects, environmental exposure to carcinogens, and individual immune system characteristics are likely to be factors that predispose individuals to develop AL.5 Polymorphisms could also explain the different incidence of AL observed between the genders.Genetic polymorphisms in the drug-metabolizing enzymes are extremely common and may contribute to the risk of developing cancers. These polymorphisms could explain differences in the way in which individuals metabolize chemical agents.6 Studies have included polymorphisms of genes coding for P450 cytochromes (CYP), which are involved in phase I of metabolism (oxidation/activation). Most polymorphisms described for these genes, such as T6235C of CYP1A1 (CYP1A1*2A), C-1019T of CYP2E1 (CYP2E1*5B), and -A290G of CYP3A4 (CYP3A4*1B), are believed to cause an increase in enzymatic activity. They have been implicated in the bioactivation of several chemical carcinogens and the conversion of polyaromatic hydrocarbons from tobacco smoke into intermediate reactive metabolites, some of which can damage DNA.7 Glutathione Smethyl transferases (GST) are implicated in phase II of metabolism (conjugation/detoxification). Two widespread genetic polymorphisms that involve deletions in the GSTT1 and GSTM1 ge...

RAD51 and XRCC3 Gene Polymorphisms and the Risk of Developing Acute Myeloid Leukemia

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Sex and Gender Differences in Hematology

“…For example, quinone oxoreductase*2 homozygosity is associated in males below 30 or over 50 years of age with the AML M3 FAB subtype but not in females. 42 The gender difference in AML is lowest in the age group 30-50 years. This might be one explanation why men have a higher risk to develop AML, depending on age.…”

Gender divergent expression of Nqo1 in Sprague Dawley and August Copenhagen x Irish rats

“…In addition to carcinogen exposure, an individual's unique immune system, diet, and genetic polymorphisms may play a role in susceptibility to developing acute leukemia. It has been proposed that gender, in combination with polymorphisms, may affect the risk of acquiring acute leukemia, since researchers have found that males with the NQO1*2 homozygous and del(GSTT1) polymorphisms are at a higher risk of acquiring acute leukemia than females with these polymorphisms [26].…”