CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome (original) (raw)
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Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia
American Journal of Hematology, 2005
The involvement of phase I and II enzymes is well documented in the metabolism of a wide range of drugs and xenobiotics. Single-nucleotide polymorphisms (SNPs) of these enzymes are also known to alter their protein expression and function. Moreover, genetic susceptibility and environmental exposure have been proposed to be an etiology of cancer. We hypothesized that polymorphisms of these enzymes might affect the risk of childhood acute lymphoblastic leukemia (ALL). CYP 1A1, CYP 3A4*1B, CYP 3A5*3, CYP 3A5*6, GSTM1, and GSTT1 polymorphisms were genotyped by using PCR-RFLP in 107 children with ALL and 320 healthy controls. Allele and genotype frequencies of each of the SNPs were compared between two groups. It was found that the allele frequencies of CYP 1A1*1, *2A, *2B, and *4 were not different between cases and controls. CYP 3A4*1B allele frequency was only 0.8% and 0.9% in ALL and controls, respectively. CYP genotype frequencies showed no statistically significant difference between patients and controls. CYP 3A5*6 was not detected in our population. The GSTM1 null genotype was significantly increased in children with ALL (OR 1.7; 95% CI, 1.0, 2.7). In contrast, the GSTT1 null genotype did not show this effect. Our data thus demonstrate that the GSTM1 null genotype might increase the risk of childhood ALL in a Thai population. Am.
Oncology, 2007
investigate the possible association of CYP2E1 * 5B, * 6 and * 7B alleles, alone or in combination, with the risk of incidence of childhood ALL in a Turkish population. Methods: The genotypes for both polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism techniques on 207 healthy controls and 168 patients. Results: Neither locus was associated with the occurrence of childhood ALL. On the other hand, when both CYP2E1 * 5B and * 6 alleles were considered together, the risk of childhood ALL increased significantly (2.9-fold; OR = 2.9, 95% CI 1.0-8.5; p ! 0.05). Moreover, the presence of at least 2 variant alleles of any combination increased the risk significantly 3.9 times, suggesting a combined effect (OR = 3.9, 95% CI 1.4-11.0). Conclusion: Individuals carrying combinations of CYP2E1 * 5B , * 6 and * 7B variants together are likely associated with the risk of developing childhood ALL.
Pakistani Journal of Medical and Health Sciences, 2020
Background: A combination of risk factors effecting of genetic susceptibility and environmental exposure may explain the multi-step process of carcinogenesis/leukemogenesis of acute myeloid leukemia (AML). Aim: To evaluate the role of genetic polymorphisms of human cytochrome P450, namely CYP1A1 & CYP2D6 enzymes, involved in the transformation of chemical and cellular metabolism of drugs and carcinogenic agents as risk factors for AML Sudanese patients. Methods: A case control study was conducted between June 2016and June 2018 at the Radiation and Isotope Center Khartoum (RIKA), Sudan. A total of 265 blood specimens (200AML patients and 65 controls) were investigated for allele frequency and genotypes of CYP1A1*2C and CYP2D6*4. The DNA was extracted from all blood specimens, using Qiagen DNA extraction kit. Standard polymerase chain reaction and Restriction fragment length polymorphism analysis (PCR-RFLP) methods were used for genotyping. Results: Although no significant variations were evident for CYP1A1 AG genotype, the GG genotype showed significant differences. We also found no difference in frequencies of alleles A and G of gene CYP1A1 between patients. While, there is evidence of increased frequency when compared with control G allele. The genotype of the CYP2D6*4 allele revealed no significant differences between IM (heterozygous) and the mutant homozygous (PM) genotype. The PM allele for the CYP 2D6 gene was high in both patients and controls. Conclusions: Our findings illustrate that the genetic polymorphisms for xenobiotic metabolizing enzymes CYP1A1 heterozygous AG reveal no significant association with AML, where homozygous GG shows a protective effect. CYP2D6 suggests no association with the risk of AML for both heterozygous IM and the mutant homozygous PM.
Asian Pacific journal of cancer prevention : APJCP, 2017
Aim: Cytochrome P450 (CYP) enzyme catalyzes the phase I metabolism reaction which metabolize endogenous and exogenous DNA-reactive chemical compounds and xenobiotics which could induce genotoxicity and increase the risk for leukemia. We aimed to detect frequency of CYP3A5*3 and CYP1A1*2C polymorphisms in Egyptian acute myeloid leukemia (AML) patients and to determine role of allele’s variants as a risk factor for developing leukemia. Patients and Methods: A case-control study was conducted on seventy acute myeloid leukemia patients and thirty control subjects. Samples were analyzed for prevalence of CYP3A5*3 and CYP1A1*2C polymorphisms using PCR - restriction fragment length polymorphism method. Results: CYP3A5*3 polymorphism (3/3) and (1/3) genotype were significantly elevated in AML group compared to control group (p=0.002). However, no statistical significant differences were found between patients and control group as regard CYP1A1*2C polymorphism. Conclusion: Our results sugges...
Blood Cells Molecules and Diseases, 2008
The effects of the CYP1A1⁎2A genotype on susceptibility to leukemia have received particular attention in recent years because this enzyme plays a central role in the activation of carcinogens. Several polymorphisms at the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We evaluated the role of the CYP1A1⁎2A genotype in adults with acute lymphoblastic leukemia (ALL) by genotyping 210 patients and 228 healthy controls from the Mexican population. The frequency of the CC genotype was 8% (18/228) in the control group and 42% (88/210) in ALL patients; the frequency of the CT genotype was 39% (89/228) and 29.5% (62/210), respectively; and that of the TT genotype was 53% (121/228) and 28.5% (60/210), respectively. The odds ratio was 8.4 (95% CI, 4.7–15.5; P < 0.001). These data indicate that the CYP1A1⁎2A genotype contributes significantly to susceptibility to adult ALL in a sample of the Mexican population.
Genetic polymorphism of GST, NAT2, and MTRR and susceptibility to childhood acute leukemia
Molecular Biology, 2008
Polymorphisms in genes coding xenobiotic-metabolizing enzymes are considered as risk factors modifying susceptibility to cancer. We developed a biochip for the analysis of 18 mutations in 10 genes of metabolizing system: CYP1A1, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, CYP2C9, CYP2C19, and NAT2. Using allele-specific hybridization on the biochip 76 T-cell non-Hodgkin's lymphoma (NHL) patients, 83 B-cell chronic lymphocytic leukemia (B-CLL) patients, and 177 healthy donors were tested. Polymorphic CYP1A1 alleles were more frequent in B-CLL patients relative to normal controls, for example, a combination of polymorphic variants 4887C > A, 4889A > G, and 6235T > C (OR 5 1.76, 95% CI 5 1.0-3.1). The GSTM1 null genotype was more frequent in NHL patients relative to controls (OR 5 1.82, 95% CI 5 1.1-3.1). The combination of unfavorable polymorphic CYP1A1 variants and GSTM1 null genotype was found more frequently in B-CLL patients relative to controls (OR 5 2.52, 95% CI 5 1.3-4.9). In addition, male B-CLL patients demonstrated a significantly increased occurrence of heterozygous and homozygous allele *2 of CYP2C9 gene (OR 5 2.38, 95% CI 5 1.1-5.2) as well as a combination of alleles *2 and *3 of the gene (OR 5 2.09, 95% CI 5 1.1-3.9). Thus, our findings show the association between polymorphic alleles of CYP1A1, GSTM1, and CYP2C9 genes and the risk to develop NHL or B-CLL. The developed biochip can be considered as a convenient analytical tool for research studies and predictive analysis in oncohematology. Am. J. Hematol.
Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias
Carcinogenesis, 1999
Xenobiotic-metabolizing enzymes constitute an important line of defence against a variety of carcinogens. Many are polymorphic, constituting the basis for the wide interindividual 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.
Cancer Epidemiology Biomarkers & Prevention
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. In utero and postnatal exposures to various carcinogens may play a role in the etiology of this disease. N-acetyltransferases, encoded by the NAT1 and NAT2 genes are involved in the biotransformation of aromatic amines present in tobacco smoke, environment, and diet. Their rapid and slow acetylation activity alleles have been shown to modify the risk to a variety of solid tumors in adults. To investigate the role of NAT1 and NAT2 variants as risk-modifying factors in leukemogenesis, we conducted a case-control study on 176 ALL patients and 306 healthy controls of French-Canadian origin. Slow NAT2 acetylation genotype was found to be a significant risk determinant of ALL (odds ratio, 1.5; 95% confidence interval, 1.0 -2.2) because of overrepresentation of the alleles NAT2*5C and *7B and underrepresentation of NAT2*4. Besides a slight increase in NAT1*4 allele frequency among cases, no independent association of NAT1 acetylation genotypes and ALL risk was observed. However, the risk associated with NAT2 slow acetylators was more apparent among homozygous individuals for NAT1*4 (odds ratio, 1.9; 95% confidence interval, . When NAT2 slow acetylators were considered together with the other risk-elevating genotypes, GSTM1 null and CYP1A1*2A, the risk of ALL increased further, which showed that the combination of these genotypes is more predictive of risk then either of them independently. These findings suggest that leukemogenesis in children is associated with carcinogen metabolism and consequently related to environmental exposures. The abbreviations used are: ALL, acute lymphoblastic leukemia; GSTM1 and GSTT1, glutathione-S-transferase M1 and T1; CYP1A1, cytochrome P450 1A1; NAT1 and NAT2, N-acetyltransferases 1 and 2; OR, odds ratio; CI, confidence interval; WT, wild type.