Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The genetic factors underlying the susceptibility to this disease remain elusive. The enzymes CYP2E1, MPO and NQO1 are involved in the biotransformation of a variety of xenobiotics present in organic solvents, tobacco smoke, drugs, plastic derivatives and pesticides. They also control the level of the oxidative stress by catalyzing the formation of free radicals or by protecting cells from their deleterious effect. DNA variants in the corresponding genes have been associated with an increased susceptibility to different adult cancers, including hematologic malignancies. To investigate whether they represent risk-modifying factors in childhood ALL, we conducted a case-control study involving 174 patients and 337 controls, both of French-Canadian origin. We found that carriers of the CYP2E1*5 variant were at 2.8-fold higher risk of ALL (95%CI, 1.2-6.4) and that NQO1 alleles *2 and *3 contributed to the risk of ALL as well (OR ؍ 1.7, 95%CI, 1.2-2.4). No such association was found with MPO alone. However, when the wild-type MPO allele was considered together with the CYP2E1 and NQO1 risk-elevating genotypes, the risk of ALL was increased further (OR ؍ 5.4, 95%CI, 1.2-23.4) suggesting a combined effect. We also found a gene-gene interaction between the GSTM1 null genotype and NQO1 mutant alleles. It is therefore plausible that exposure to xenobiotics metabolized by these enzymes play a role in the etiology of childhood ALL. © 2002 Wiley-Liss, Inc.
Key words: genetic polymorphism; quinone oxidoreductase; myeloperoxidase; cytochrome P-450; acute lymphoblastic leukemia; cancer geneticsAcute lymphoblastic leukemia (ALL) is the most frequent form of cancer affecting children. Sporadic cancer, such as ALL, may be considered a complex disease in which the individual's risk of cancer represents a cumulative effect of a series of low-penetrance genes combined with the external factors. For example, the interindividual variability in the cancer susceptibility can be partly explained by inherited abilities to metabolize carcinogenic xenobiotics (reviewed in ref. 1). Children are particularly vulnerable to environmental toxicants because of their greater relative exposure, a less mature metabolism and higher levels of cell division and growth. 2 In this context, functional polymorphisms in xenobioticmetabolizing enzymes are of relevance in determining susceptibility to pediatric cancer. We recently showed that the GSTM1 null, CYP1A1*2A and NAT2 slow acetylator genotypes were significant predictors of ALL risk in children, 3,4 suggesting that polymorphisms in these genes played a role in childhood leukemogenesis. In this respect other interesting candidate genes are those encoding for enzymes controlling oxidative stress.CYP2E1 metabolizes different carcinogens, including nitrosamines, benzene, ethanol and halogenated solvents. [5][6][7] In addition, CYP2E1 effectively reduces dioxygen to free radical species, thus contributing to lipid peroxidation and o...
