title: Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias.
abstract: Xenobiotic-metabolizing enzymes constitute an important line of defence against a variety of carcinogens. Many are polymorphic, constituting the basis for the wide inter-individual variation in metabolic capacity and possibly a source of variation in the susceptibility to chemical-induced carcinogenesis. The aim of this study was to determine the existence of any association between the main genetic polymorphisms of cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1) and N-acetyltransferase 2 (NAT2) and an altered risk for haematological neoplasias. A total of 160 patients and 128 controls were genotyped by means of PCR-RFLP-based assays. Mutated alleles comprising CYP2D6*4, GSTM1*0, NAT2*5A, *5B, *5C, *6 and *7 were analysed along with the wild-type alleles. The results showed a higher frequency of CYP2D6 extensive metabolizers carrying two functional alleles in the leukaemia group, when compared with controls (76.6 versus 57.0%, P = 0.008). No differences were found in the case of Hodgkin and non-Hodgkin lymphomas. Analysis of the GSTM1 and NAT2 polymorphisms failed to show an association with any of the neoplasias, although a near significant increase in fast acetylators was also found in the leukaemia group (50.0 versus 35.9%, P = 0.06). The results suggest an association of extensive metabolism with an increased risk for leukaemia, possibly by an increase in the metabolic activation of chemical carcinogens or linkage to another cancer-causing gene. Opposite findings presented in other studies may reflect geographical differences in the type of environmental carcinogens to which different populations are exposed.
authors.affiliation: Medical Genetics Unit, Faculty of Medicine, University of Coimbra, and Department of Clinical Haematology, University Hospital of Coimbra, 3049 Coimbra Codex, Portugal.
authors.forename: M C
authors.initials: MC
authors.lastname: Lemos
authors.forename: F J
authors.initials: FJ
authors.lastname: Cabrita
authors.forename: H A
authors.initials: HA
authors.lastname: Silva
authors.forename: M
authors.initials: M
authors.lastname: Vivan
authors.forename: F
authors.initials: F
authors.lastname: Plácido
authors.forename: F J
authors.initials: FJ
authors.lastname: Regateiro
mesh_terms: D000328:Adult; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic
chemical_list: D001191:Arylamine N-Acetyltransferase; D019389:Cytochrome P-450 CYP2D6; D005982:Glutathione Transferase; C478900:NAT2 protein, human