Analysis of Common Single Nucleotide Polymorphisms in MDR1 Gene in Patients with Multiple Myeloma.

P-glycoprotein (P-gp) encoded by MDR1 gene is a xenobiotic transporter involved in protection of normal tissues against environmental toxicants and multi-drug resistance of cancer cells. Recently, a number of authors, including our group, have indicated that phenomenon of single nucleotide polymorphism (SNP) in MDR1 may influence susceptibility or prognosis in various diseases as well as pharmacokinetics of P-gp substrates. Although environmental chemicals are suspected carcinogens in multiple myeloma (MM) and P-gp transported drugs are used in the treatment of this malignancy, little data is known on the significance of MDR1 SNPs in MM. In this study, three common MDR1 SNPs: C1236T, G2677T/A and C3435T were assessed in 89 MM patients using automated sequencing and RFLP method. Moreover, in the control group of 215 healthy individuals MDR1 C3435T SNP was genotyped in all subjects and P-gp expression and activity were examined in a proportion of subjects. The haplotypes were inferred using Partition-Ligation algorithm showing highest frequency of the haplotype with wild-type alleles at all sites studied (1236C-2677G-3435C, 30%), followed by haplotype with all mutant alleles (1236T-2677T-3435T; 27%) and 1236C-2677G-3435T haplotype (12%). Carriers of a mutant allele at MDR1 1236 site showed a trend to longer overall survival as compared to wild-type homozygotes MDR1 1236CC (p=0.08), while no correlations with survival were observed regarding other polymorphisms. As compared to the control group, the MDR1 C3435T SNP allele frequency did not differ in MM patients, however the carriers of at least one T-allele (CT and TT genotypes) were significantly more frequent in the MM cohort (79% vs. 65%, p=0.02). The flow cytometry results of anti-P-gp MRK16 antibody staining and functional rhodamin123/PSC833 assay performed on peripheral blood mononuclear cells, CD19+ B-lymphocytes and CD3+ T-lymphocytes were similar among healthy individuals having MDR1 3435CC, CT and TT genotypes. In conclusion, we observed that MDR1 gene SNPs may exert some effect in genetic predisposition and prognosis in MM, which should be further examined in larger cohorts of uniformly treated patients.