In:
Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3284-3284
Abstract:
Abstract 3284 Poster Board III-1 Purpose: Imatinib resistance is a major cause of imatinib treatment failure in chronic myeloid leukemia (CML) patients. In our previous study (Clin Cancer Res, 2009, 15(14):4750–8), SNP markers in the pathways of imatinib metabolism / transport could predict the response and resistance of imatinib therapy in CML. It has been known that organic cationic transporter-1 gene (OCT1, SLC22A1) is regulated by HNF4A (hepatocyte nuclear factor 4-alpha) or by PPARA (peroxisomal proliferators-activated receptor alpha) or PPARD (PPAR-delta). In addition, DNA repair machinery such as NER (nucleotide excision repair) or DSB (double strand break) repair pathway, plays an important role in the action mechanism of imatinib, in which ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5), or XRCC4 (X-ray repair complementing defective repair in Chinese hamster cells 4), were involved. The response to imatinib therapy in chronic myeloid leukemia (CML) is various according to inter-individual variation of drug delivery or metabolism. Thus, the current study investigated SNPs in the candidate genes involved in the imatinib transport/metabolism pathway and DNA repair enzyme pathway, and its association with clinical outcomes following imatinib therapy in CML patients. Methods: In the current study, we investigated 81 SNPs markers involved in the pathways of imatinib transport/metabolism pathway (n=62; ABCB1, ABCG2, CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP3A4, CYP3A5, AGP, OCT1, PPARA, PPARD, HNF4A) and DNA repair enzyme pathway (n=19; ERCC1/2/4/5, XRCC1/2/4/5). Total of 187 CML patients treated at the Samsung Medical Center, Chonnam National University Hwasun Hospital, or Kyungpook National University Hospital, Korea, were enrolled into the study. The DNAs from peripheral blood samples were genotyped with MALDI-TOF based technique (Sequenom). Results: Among the SNP markers involved in imatinib transport/ metabolism pathway, HNF4A (rs3212172) was significantly associated with high risk of loss of response (LOR; p 〈 0.001) or treatment failure (p=0.013). CYP1A2 (rs762551) was significantly associated with high risk of LOR (p 〈 0.001) or treatment failure (p=0.035). In addition, ERCC5 (rs17655) showed significant association with response (p=0.036 for complete cytogenetic response [CCR], 0.024 for major molecular response [MMR] ) or with resistance (p=0.05 for LOR, 0.025 for treatment failure), while XRCC4 (rs963248) showed significantly consistent association with response to imatinib (p=0.025 for major cytogenetic response [MCR], 0.032 for CCR, 0.008 for MMR, and 0.06 for complete molecular response [CMR] ). External validation is now ongoing and the result will be presented in the meeting. Conclusions: The current study suggested that SNP marker on HNF4A gene, regulator of OCT1 gene expression, could predict the risk of resistance to imatinib therapy, and that SNP markers on ERCC5 or XRCC4, involved in the NER and DSB repair pathway, also could predict the response to imatinib therapy, suggesting a potential involvement of DNA repair machinery in the action mechanism of imatinib in CML. Disclosures: No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V114.22.3284.3284
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2009
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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