1728

NQO1

DHQU|DIA4|DTD|NMOR1|NMORI|QR1;NAD(P)H dehydrogenase, quinone 1;NQO1;NAD(P)H dehydrogenase, quinone 1

DT-diaphorase|NAD(P)H dehydrogenase [quinone] 1|NAD(P)H:Quinone acceptor oxidoreductase type 1|NAD(P)H:menadione oxidoreductase 1|NAD(P)H:quinone oxidoreductase 1|NAD(P)H:quinone oxireductase|azoreductase|diaphorase (NADH/NADPH) (cytochrome b-5 reductase)

16q22.1

protein-coding

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 associatedwith 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) andthat 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 thewild-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.#CI- Copyright 2002 Wiley-Liss, Inc.

The origin of acute lymphoblastic leukemia (ALL), the most common pediatric cancer, can be explained by a combination of genetic factors and environmental exposure. The environmental toxicants to which an individual is exposed are biotransformed and eliminated from the body after metabolic conversion mediated by Phase I and Phase II xenobiotic-metabolizing enzymes. Phase I enzymes catalyze hydroxylation, reduction and oxidation reactions of xenobiotics (carcinogens/drugs), often converting them into more active or toxic compounds. Phase II enzymes catalyze conjugation reactions (glucuronidation, acetylation, methylation), thereby converting the metabolites into non-reactive, water-soluble products that are eliminated from the organism. The genetic polymorphism underlying the variation in enzyme activity can modify susceptibility to diverseadult cancers, probably by influencing the activation and removal of toxicants or drugs. Here we present an overview of the role of genetic variants of certain Phase I and Phase II enzymes in the development of childhood ALL, a good model for such studies because of its short latency period. The genetic contribution to the development of ALL is examined by association studies that analyze the loci of Phase I enzymes (cytochrome P-450, myeloperoxidase) and Phase II enzymes (quinone-oxidoreductase, glutathione-S-transferase, N-acetyltransferase). The loci of the enzyme variants CYPlA1, CYP2E1, NQO1, GSTM1, GSTP1, NAT2 are associated with disease development, and evidence of gene-gene interactions has emerged as well. Despite the improvements in treatment, resistant cases of ALL remain a leading cause of cancer-related death in children. Although the underlying mechanism of drug resistance is not well understood, differences in the capacity of ALL patients to process drugs and environmental carcinogens could play a role by modifying the risk of recurrent malignancy, as well as the response to therapy. Therefore, polymorphic genes encoding carcinogen- and drug-metabolizing enzymes may not only increase the risk of ALL but also influence the risk of relapse in patients. We found that the prognosis of patients with CYPlA1 and NQO1 variants was worse than that of patients who lack these variants. We conclude that genotyping ALL patients for functional polymorphisms of candidate genes can become an important tool in predicting disease outcome.