Role of NQ01, MPO and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia

Abstract

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 CYP2EI*5 variant were at 2.8-fold higher risk of ALL (95%Cl, 1.2-6.4) and that NQOI alleles*2 and*3 contributed to the risk of ALL as well (OR = 1.7, 95%Cl, 1.2-2.4). No such association was found with MPO alone. However, when the wild-type MPO allele was considered together with the CYP2EI and NQOI risk-elevating genotypes, the risk of ALL was increased further (OR = 5.4, 95%Cl, 1.2-23.4) suggesting a combined effect. We also found a gene-gene interaction between the GSTMI null genotype and NQOI 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.