GENETIC LINKED TO LEUKEMIA: ROLE OF POLYMORPHISMS IN CANDIDATE GENES INTERCONNECTED TO LEUKEMIA (original) (raw)
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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...
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.
CYP1A1 and CYP2D6 Polymorphisms and Susceptibility to Chronic Myelocytic Leukaemia
Current Cancer Drug Targets, 2020
Background: CYP1A1 and CYP2D6 are both xenobiotic metabolizing enzymes belonging to the CYP450 enzyme family. Polymorphisms in these genes vary between individuals, resulting in dissimilar patterns of susceptibility to the effects of carcinogenic substances and drugs. Objective: In a prospective study, the influence of CYP1A1*2C and CYP2D6*4 gene polymorphisms on the susceptibility to chronic myelocytic leukaemia (CML) were investigated. Method: Prevalence of CYP1A1*2C and CYP2D6*4 was detected in blood specimens from three hundreds participants - two hundred patients and a hundred healthy individuals as a control group, using PCR-RFLP. Results: CYP1A1 Ile/Val and Val/Val genotype frequency in our study population was 82% & 15% in CML patients and 55% & 8% in controls, respectively. This suggests carriers had an elevated risk (OR=18.38, 95% CI=7.364-45.913, p value; =0.000 and OR=23.125,95 % CI=7.228-73.980, p value=0.000, respectively). Individuals carrying the CYP2D6 heterozygous ...
Archives of Orofacial Sciences, 2020
CYP3A4 and CYP3A5 are metabolizing enzymes abundantly expressed in liver and involved in the metabolism of xenobiotics as well as clinically used drugs. Genetic polymorphisms in CYP3A4 and CYP3A5 may alter the metabolic ability of individuals. Thus, CYP3A4 and CYP3A5 might play an important role in the aetiology of chronic myeloid leukaemia (CML) and as modulators of cancer therapy response. In this study, the impact of two single nucleotide polymorphisms (SNPs) CYP3A4*18 (878T>C) and CYP3A5*3 (6986A>G) on CML susceptibility risk was investigated. This case-control study involved a total of 520 study subjects comprising 270 CML patients and 250 normal healthy controls. Genotyping of CYP3A4*18 and CYP3A5*3 was performed by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and CML susceptibility risk was assessed by logistic regression analysis, deriving odds ratio (OR) with 95% confident intervals. The results showed that heterozygous (*1/*1*8) genotype of CYP3A4*18 was significantly associated with CML susceptibility risk (OR 3.387; 95% CI: 1.433-8.007, p = 0.005). No homozygous variant (*18/*18) genotype was detected in this study. On the contrary, homozygous variant (*3/*3) and heterozygous (*1/*3) genotypes of CYP3A5*3 were associated with significantly lower risk for CML susceptibility (OR 0.140; 95% CI: 0.079-0.246' p < 0.001 and OR 0.310; 95% CI: 0.180-0.535, p < 0.001, respectively). The results prompt us to conclude that genetic variation in CYP3A4*18 may contribute to a higher risk whereas CYP3A5*3 polymorphism confers a lower susceptibility risk in Malaysian CML patients.
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 polymorphisms of the CYP3A4, CYP3A5, CYP3A7 and CYP1A2 among the Jordanian population
Environmental Toxicology and Pharmacology, 2012
Cytochromes P450 (CYP450) plays an extremely vital role in oxidation, reduction, and peroxidation of numerous endogenous and exogenous compounds, like drugs and procarcinogens. Mainly, expression occurs in the liver, in varying polymorphic forms. Therefore, proposed as biomarkers of susceptibility to carcinogenicity and toxicity. The objective of this study was to find the allelic frequencies of CYP3A5*2,*3,*4,*5,*6,*7, CYP3A4*1B, CYP3A7*1C and CYP1A2*1C, *1D, *1E, *1F enzymes in Jordanians, and to compare them with other ethnic groups. We used polymerase chain reaction-restriction fragment length (PCR-RFLP) to genotype alleles, and we calculated frequencies using Hardy Weinberg's equation (HWE). Allelic frequencies results were: CYP3A5*2 (0.2%), CYP3A5*3 (86.6%), CYP3A5*6 (1.7%), CYP*3A5*4,*5*7 not detected, CYP3A4*1B (11.7%), CYP3A7*1C (1.7%). Finally 6.5%, 18.2%, 6.0%, 67.3% were the results of CYP1A2*1C, 1D, 1E and 1F, respectively. In conclusion, genotyping method and results of this study can be adopted or used in pharmacotherapy, toxicity and carcinogenic studies in Jordan.
Association of CYP2D6* 4 Polymorphism with Chronic Myeloid Leukemia
Journal of Medical …, 2007
Background: CYP2D6 is a xenobiotic metabolizing enzyme, belongs to CYP450 enzyme family. It metabolizes 20-25% of all the drugs. Polymorphisms in these genes will lead to inter individual variations with different patterns of susceptibility to the effects of carcinogenic substances and drugs. The aim of this study was to find the association between CYP2D6 *4 polymorphism and chronic myeloid leukemia (CML). Methods: A total of 200 CML and 200 controls were genotyped for CYP2D6*4 polymorphism using PCR-RFLP (polymerase chain reaction -restriction fragment length polymorphism) method. Results: The genotypic frequencies were compared between CML and controls. There was slight increase in the IM genotype frequency among CML cases. Increased frequency of PM genotype (2.06%) was observed in males. When comparison was made with respect to phase of CML, IM genotype frequency was elevated in blast crisis phase (36.36%). With respect to drug response IM genotype and P allele frequency were increased in partial resistant and complete resistant cases as compared to good responders. Interpretation: This study reveals the possible role of CYP2D6*4 polymorphism in the progression of CML. JMSR • OCTOBER 15, 2007 • 1 (1)
Association of CYP3A4 genotype with treatment-related leukemia
Proceedings of the National Academy of Sciences, 1998
Epipodophyllotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment-related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0. 016, FET). This relationship remained significant when 19 treatment-related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.
The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique
Cytochrome P450 2C19 (CYP2C19) participates in the metabolism of many clinically important drugs and xenobiotic compounds. Genetic polymorphisms of the CYP2C19 gene are described to have possible effect on drug treatment and increasing susceptibility to carcinogenic substances. The aim of this study was to determine the frequencies of the common polymorphic CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) in Gaza Strip population and to investigate their association with occurrence of childhood hematological malignancies as compared to healthy subjects. The polymorphism of CYP2C19 was analyzed by PCR-RFLP. DNA was extracted from blood samples obtained from 52 previously diagnosed hematological malignancy children and 200 normal subjects. In the patient group the frequencies of CYP2C19*2 and CYP2C19*3 were 9.62% and 0.96%, respectively; while in the control group the respective frequencies were 5.75% and 3%. There is no significant difference between the healthy and the patient groups in te...