PROGNOSTIC VALUE OF CYP3A5 AND hOCT1 POLYMORPHIC GENE VARIANTS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN THE REPUBLIC OF BASHKORTOSTAN

Introduction. Patients suffering from chronic myeloid leukemia (CML) demonstrate various degrees of therapeutic effect after treatment using tyrosine kinase inhibitors (TKI). The response is determined by the presence or absence of mutations in the BCR-ABL gene, as well as by the mutation type.

Aim. To establish the prognostic value of polymorphic variants of genes involved in the metabolism of TKI — CYP3A5 and hOCT1 — in patients with CML in the Republic of Bashkortostan (RB).

Materials and methods. A series of genetic studies was performed in 114 patients with a clinically and cytogenetically established diagnosis of chronic myeloleukemia (CML), among whom 55 and 59 were men and women, respectively, with the median age of 43 years, from 14 to 76 years. All the patients received TKI treatment according to national clinical guidelines and European Leukemia Net criteria. In order to compare patients with different treatment efficiencies, a group of 64 patients resistant to the therapy was formed. The groups under comparison were similar in gender and age. An analysis of polymorphic DNA loci of the hOCT1 and CYP3A5 genes was carried out using polymerase chain reaction of DNA synthesis and RFLP analysis followed by electrophoresis in 7–8 % polyacrylamide gel.

Results. No significant differences were found in the frequency distribution of alleles and genotypes of the rs776746 polymorphic locus of the isoenzyme P3A5 cytochrome p450 (CYP3A5) gene (p > 0.05) between CML patients with different TKI treatment efficiencies. When comparing the frequency distribution of alleles and genotypes of the rs683369 polymorphic variant in the (hOCT1) organic cation carrier gene, the *C*C genotype was established to be statistically significantly more frequent in patients with an optimal response to treatment compared to those treatment resistant. The frequency of occurrence of the *С*G genotype was almost two times higher in CML patients resistant to therapy and comprised 42.86 %, compared to the group of patients with an optimal response to TKI treatment with the value of 21.88 %.

Conclusions. In CML patients, in contrast to rs776746 of the CYP3A5 gene, the study of the rs683369 polymorphic locus of the hOCT1 gene has a prognostic value for assessing the efficacy of TKI treatment. The frequency of occurrence of the *C*G genotype was significantly higher in CML patients resistant to TKI therapy, while the G*G* genotype was less common and associated with the shortest life expectancy. The presence of the C*C* genotype was favourable for the overall survival of patients.

chronic myeloleukemia, epidemiology, mutations, CYP3A5 and hOCT1 gene polymorphism, tyrosine kinase inhibitors, resistance, prognosis, survival

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