title: Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia.
abstract: The significance of genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Polymorphisms of genes encoding for xenobiotics and drug transporters are potential factors, which can influence the risk of developing ALL and its clinical outcome. P-glycoprotein (P-gp) is an adenosine triphosphate-binding cassette (ABC)-family transporter involved in protection against xenobiotics and multi-drug resistance. Recently, the single-nucleotide polymorphism C3435T of MDR1 gene has been found to be associated with altered tissue expression and function of P-gp. To evaluate whether C3435T MDR1 polymorphism is associated with the occurrence and outcome of ALL, 113 children with ALL (median age 5.1 yr) and 175 healthy individuals of Polish Caucasian origin were studied by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assay. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (OR, 95% CI; 1.8, 1.1-3.1; P = 0.037). Besides, the analysis of factors influencing clinical outcome of our ALL patient cohort showed that CC genotype carriers had significantly lower event-free survival probability (pEFS) (0.62 vs. 0.87; P = 0.007) and overall survival probability (pOS) (0.72 vs. 0.91; P = 0.006). The Cox proportional hazards model-based analysis revealed that the hazard ratios for lower pEFS and lower pOS among CC homozygous subjects were 3.9 (P = 0.008) and 3.3 (P = 0.02), respectively. In conclusion, the results of the present study provide evidence that C3435T MDR1 polymorphism may involve both the susceptibility to and the clinical outcome of childhood ALL. Carriers of the TT genotype are more at risk of developing ALL than other individuals, whereas CC genotype carriers are supposed to have worse prognosis.
authors.affiliation: Department of Haematology, Medical University of Lodz, ul. Pabianicka 62, 93-513 Lodz, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jamroziak
authors.forename: Wojciech
authors.initials: W
authors.lastname: Młynarski
authors.forename: Ewa
authors.initials: E
authors.lastname: Balcerczak
authors.forename: Magda
authors.initials: M
authors.lastname: Mistygacz
authors.forename: Joanna
authors.initials: J
authors.lastname: Trelinska
authors.forename: Marek
authors.initials: M
authors.lastname: Mirowski
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bodalski
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D019450:Genes, MDR; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D015993:Life Tables; D008297:Male; D020125:Mutation, Missense; D017354:Point Mutation; D011044:Poland; D012150:Polymorphism, Restriction Fragment Length; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D012306:Risk; D044465:White People / Q000235:genetics