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

Document Type: Research Articles

Authors

1 Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Egypt.

2 South Egypt Cancer Institute, Assiute University, Egypt.

Abstract

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

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