title: Genetic variations of hOCT1 gene and CYP3A4/A5 genes and their association with imatinib response in Chronic Myeloid Leukemia.
abstract: There is an increasing body of evidence demonstrating that mechanisms independent of BCR/ABL gene also contribute to imatinib resistance in Chronic Myeloid Leukemia (CML). It has been extensively reported that polymorphisms of the genes associated with imatinib metabolization and imatinib influx/efflux play an important role in the disease resistance. We investigated the impact of 12 genetic variants of the two genes, CYP3A4/A5 and the human cation transporter 1 gene (hOCT1) on the clinical outcome, in a cohort of 106 newly diagnosed CML patients. In the patient cohort investigated, only 6 variant alleles could be detected. The others were not present and could not be investigated. Two polymorphisms, CYP3A5*3 (rs776746)and hOCT1 M408V (rs628031), were significantly associated with the Complete Cytogenetic Response (CCyR) at 6 months and Major Molecular Response (MMR) at 12 months. The presence of favourable alleles at M408V and M420del in combination was associated with a MMR at 12 months. Functional polymorphisms of the genes associated with imatinib influx and metabolization may play a role in predicting primary response to imatinib and treatment outcome.
authors: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India.
authors: Shantashri
authors: S
authors: Vaidya
authors: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India.
authors: Kanjaksha
authors: K
authors: Ghosh
authors: Department of Haematology, 10th Floor, New Multistoried Building, KEM Hospital, Parel, Mumbai 400012, India.
authors: Chandrakala
authors: C
authors: Shanmukhaiah
authors: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India. Electronic address: vbaburao@hotmail.com.
authors: Babu Rao
authors: BR
authors: Vundinti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D027702:Organic Cation Transporter 1; D000068877:Imatinib Mesylate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4/A5; Chronic myeloid leukemia; Genotyping; Imatinib resistance; hOCT1