High Risk of Acute Myeloid Leukemia in Individuals with NAD(P)H:Quinone Oxidoreductase 1 (NQO1) and Cytochrome P450 A1 (CYP1A1) Gene Defects.

Acute myeloid leukemia (AML) has been linked to chronic exposure to benzene and tobacco’s polycyclic aromatic hydrocarbons (PAH). NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that detoxifies benzene-derived quinones and reduces oxidative stress in hematopoietic cells. A C→T substitution polymorphism at nucleotide 609 of the NQO1 gene has been linked to a decreased activity of the coded enzyme. On the other hand, PAH are bioactivated by the cytochrome P450 A1 (CYP1A1) enzyme. An A→G substitution polymorphism at nucleotide 4889 and a T→C substitution at nucleotide 6235 of the CYP1A1 gene lead to the production of an enzyme with increased activity in PAH metabolism. Moreover, environmental-related diseases resulting from exposure to benzene and tobacco-related diseases have been described as serious health problems in south-eastern Brazil. The aim of this study was to evaluate the influence of the NQO1 C609T and CYP1A1 A4889G and T6235C polymorphisms for AML risk in individuals of the south eastern region of Brazil. Genomic DNA from 133 AML patients (median age: 47 years, range: 17-89; female: 63, male: 70; Caucasians: 112, African-Americans: 21) and 133 gender and race-matched controls (median age: 53, range: 25–60; female: 63, male: 70; Caucasians: 116, African-Americans: 17) were analysed using the polymerase chain reaction (PCR) and enzymatic digestion with the Hinf1, MspI, and BsrDI, respectively. The differences between groups were calculated by the chi-square or Fischer exact test. Crude odds ratios (ORs) were calculated and were given within 95% confidence intervals (CI). Logistic regression analysis was used to obtain age-adjusted ORs. P≤ 0.05 were considered statistically significant. Control samples (X²= 3.69, P= 0.07), but not patient samples (X²= 6.52, P< 0.02), were in Hardy-Weinberg equilibrium at the NQO1 C609T locus. Both patient and control samples confirmed the Hardy-Weinberg expectations at the CYP1A1 A4889G (X²= 2.54, P= 0.12; X²= 0.89, P= 0.34) and T6235C (X²= 1.06; P= 0.30; X²= 0.04; P= 0.84) loci. The frequency of the NQO1 609CT+TT genotype (41.4% vs 28.6%, P= 0.04) and the CYP1A1 6235TC+CC genotype (51.1% vs 28.6%, P= 0.0001) was significantly higher in AML patients than in controls. Therefore, carriers of the NQO1 variant allele (T) were under a 1.7-fold increased risk of AML (95% CI: 1.01-2.89) and carriers of the CYP1A1 T6235C variant allele (C) were under a 2.8-fold increased risk of the disease (95% CI: 1.67–4.84). Similar frequencies of the CYP1A1 4889AG+GG genotype were seen in patients and controls (43.6% vs 30.8%, P= 0.10). Similar risks for the disease were seen in carriers and non-carriers of the variant allele (G) (95% CI: 0.92-2.60). The combined frequency of the variant genotypes NQO1 609CT+TT and CYP1A1 6235TC+CC and 4889AG+GG was higher in AML patients than in controls (8.3% vs 1.5%, P< 0.001). Carriers of the three variant alleles were under a 11.8-fold increased risk of AML (95% CI: 2.40-57.61). The results of our study suggest that the inherited genotypes of polymorphisms involved in the pathways of carcinogens metabolism, NQO1 C609T, and CYP1A1 A4889G and T6235C, substantially alter the risk for AML in individuals of south eastern Brazil. Financial support: CNPq