期刊
ONCOTARGET
卷 4, 期 10, 页码 1582-1591出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1050
关键词
CML; Imatinib; SNPs; ABCG2; Pharmacogenetic; molecular response; BCR-ABL
资金
- Intergroup pour la Leucemie Myeloide Chronique
- INSERM (Pharmacogenetic-REPAC Network)
- ECOS-Sud program (France-Uruguay) [U03S03]
- Association Jean Bernard, France
- French Ministry of Health [11N28]
- BMS
- Novartis
Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including patients sampled from the 400 mg/d and 600 mg/d arms of the prospective SPIRIT trial (n=239). Twelve SNPs discriminating patients according to cumulative incidence of major molecular response (CI-MMR) were identified within the exploratory cohort. Three of them, all located within the ABCG2 gene, were validated in patients included in the 400 mg/d arm of the SPIRIT trial. We identified an ABCG2 haplotype (define as G-G, rs12505410 and rs2725252) as associated with significantly higher CI-MMR in patients treated at 400 mg/d. Interestingly, we found that patients carrying this ABCG2 favorable haplotype in the 400 mg arm reached similar CI-MMR rates that patients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be influenced by constitutive haplotypes in drug transporter genes. Lower response rates associated with non- favorable ABCG2 haplotypes may be overcome by increasing the imatinib daily dose up to 600 mg/d.
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