Role of NQO1, 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 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...

La leucémie de l’enfant

“…Nous avons démontré que la présence de l'allèle CYP1A1*2A (T6235C) augmentait de 80 % le risque d'apparition de la LLA (OR = 1,8 ; 95 % IC 1,1-3,1 ; p = 0,03) chez les enfants [2]. Nous avons également observé que les enfants porteurs de l'allèle CYP2E1*5 (G1259C) étaient plus susceptibles d'être atteints de LLA (OR = 2,8 ; 95 % IC 1,2-6,7 ; p = 0,03) [11]. Les glutathion-S-transférases (GST) forment une famille d'enzymes multifonctionnelles qui se divise en plusieurs classes, GSTA1, GSTM1, GSTP1, GSTS1 et GSTT1, chacune ayant une spécificité de substrats plus ou moins stricte et un profil d'expression tissulaire propre [12].…”

“…Les niveaux d'activité de NQO1 peuvent être reliés à au moins deux polymorphismes génétiques, une transition C vers T en position -465 et une autre transition C vers T en position -609 responsables, pour l'une, d'une diminution et pour l'autre, d'une perte de fonction [25]. Nous avons montré que les sujets porteurs des variants NQO1*2 ou *3 présentent un risque plus élevé de développer une LLA (OR : 1,7 ; IC95 % : 1,2-2,4 ; p = 0,004) [11]. De plus, les individus hétérozygotes présentent une activité enzymatique diminuée suggérant ainsi que de faibles niveaux d'activité de NQO1 pourraient conférer une susceptibilité accrue à la LLA.…”

“…Aucun effet additionnel n'a pu être mis en évidence avec l'allèle sans GSTT1. L'intervention des enzymes CYP2E1, NQO1 et MPO dans des voies métaboliques communes [21] nous a aussi incités à analyser l'effet combiné de leurs génotypes [11]. On observe que le risque total de LLA est accru en présence de plusieurs génotypes porteurs de risque …”

NAD (P) H Quinine Oxidoreductase (NQO1) as a Risk Modifier of Susceptibility to Polycythaemia Vera in Sudan

“…Although JAK2 gene mutations are the primary genetic abnormality in the PV that has a direct association with the pathogenesis of the disease, many other genetic abnormalities have been reported to be a risk factor in PV example TET2, NFE2 and NQO1 genes [7][8][9].NQO1 gene is located in the long arm of chromosome 16 (16q22.1), it expands approximately 20 kb with 6 exons and 5 entrons that code for NQO1 protein, a flavoenzyme mainly cytosolic enzyme formed of 273 amino acid IJBR (2015) 6 (06) www.ssjournals.com residues, that plays necessary role in the protection against exogenous and endogenous quinone by catalyzing two and four electron reduction of these substrates, such as hydroquinone [10][11][12]. NQO1 enzyme has many functions that include protection of the cells from oxidative damage, scavenging of superoxide, stabilization of p53 and other tumour suppressors and detoxification of quinone and their derivatives [11].…”

“…NQO1 enzyme has many functions that include protection of the cells from oxidative damage, scavenging of superoxide, stabilization of p53 and other tumour suppressors and detoxification of quinone and their derivatives [11].…”