Association of C3435T, C1236T and C4125A Polymorphisms of the MDR-1 Gene in Egyptian Children with Acute Lymphoblastic Leukaemia

Abstract

Background: P-glycoprotein (P-gp), a membrane transporter encoded by the multidrug resistance-1 (MDR1) gene,<br />influences pharmacokinetics and metabolism of anticancer drugs and contributes to multidrug resistance phenotype<br />in acute lymphoblastic leukemia (ALL). Genetic variation ofMDR1 in ALL patients is increasingly recognized as<br />a factor influencing response to treatment. Aim: To investigate the possible role of MDR-1 gene polymorphisms<br />(C3435T, C1236T and C4125A) as risk factors for the development and clinical outcome of ALL in Egyptian children.<br />Materials and Methods: Genotyping of MDR-1 C3435T, C1236T and C4125A single nucleotide polymorphisms<br />(SNPs) was accomplished using a polymerase chain reaction–restriction fragment length polymorphism (RFLP-PCR)<br />assay with 120 childhood ALL patients and 100 healthy controls. Results: Homozygous T with the C3435T SNP showed<br />a protective effect as compared to homozygous C (OR=0.748) while heterozygous CT correlated with a poor outcome<br />(high risk, drug unresponsiveness, relapse and high percentage of death). Additionally, the T allele of the C1236T SNP<br />showed a significant relation with ALL risk (OR=1.6). However, there were no significant differences in the genotype<br />and allele frequencies of MDR-1 SNPs between patients and controls. Only one genotype (CC) and one allele of<br />MDR-1 (C4125A) were seen. Neither CA/AA genotypes nor A alleles were present in ALL patients and normal controls.<br />TC was the predominant haplotype in both groups, while CT proved to be minor. The cumulative incidence of relapse<br />was higher with the CC genotype of C1236T as compared with TT. Conclusion: From our preliminary data, the CT<br />genotype of C3435T is associated with a poor ALL outcome while the CC genotype of C1236T is related with an<br />increased incidence of relapse. Although our results provide assistance for oncologist choice of individual therapeutic<br />strategy taking the patient genetic repertoire into consideration, further investigations with larger sample size should<br />be conducted to validate our results.