Polymorphisms of ERCC1 and ERCC5 genotypes were associated with response to imatinib therapy in chronic phase chronic myeloid leukemia

Abstract

Purpose: Imatinib resistance is a major cause of treatment failure in chronic myeloid leukemia (CML) patients. DNA repair machinery, such as nucleotide excision repair (NER) or double strand break (DSB), was known to be involved in the action mechanism of imatinib. This study evaluated 19 SNPs in ERCC and XRCC genes, and their association with imatinib response and the risk of resistance in Korean patients. Methods: Nineteen SNP markers (ERCC1/2/4/5, XRCC1/2/4/5) involved in the DNA repair enzyme pathway were investigated. A total of 169 chronic phase CML patients from 3 hospitals in Korea were enrolled in the study. DNAs from peripheral blood samples were genotyped using a MALDI-TOF based technique. Results: Among candidate SNP markers involved in the DNA repair pathway, ERCC1 (rs11615) and ERCC5 (rs17655) showed significant associations with response to imatinib therapy. The group with the TT genotype of ERCC1 (rs11615) showed a higher probability of achieving major cytogenetic response (MCR) (p=0.021, HR 3.04 [95% C.I. [1.19-7.81]), complete cytogenetic response (CCR) (p=0.035, HR 2.76 [95% C.I.1.07-7.13]), and major molecular response (MMR) (p=0.001, HR 5.48 [95% C.I. 2.05-14.6]) than those with CC or CT. The CC or CG genotype of ERCC5 (rs17655) were associated with lower risk of treatment failure (TF) (p=0.025 HR 0.40 [95% C.I. 0.18-0.89]) than those with the GG genotype. Conclusion: This study suggested that SNP markers on ERCC1 and ERCC5 involved in the NER pathway could predict the response to imatinib therapy, proposing a potential involvement of DNA repair machinery in the action mechanism of imatinib in CML.;목적: Imatinib 의 불응성은 만성골수성백혈병(chronic myeloid leukemia; CML) 의 치료 실패의 주요원인이다. 뉴클레오티드 절단복구(nucleotide excision repair;NER) 나, 이중 염색체 절단(double strand break; DSB)과 같은 DNA 복구기작은 imatinib의 작용기전에 관련된 것으로 알려져 있어, 본 연구에서는 만성기의 만성골수성백혈병 환자에서 imatinib 치료 후의 결과와 DNA 복구기작과 관련된 후보유전자의 단일염기다형성(single nucleotide polymorphism; SNP)과의 관계를 알아보고자 하였다. 방법: 본 연구에서는 DNA 복구와 관련된 효소경로에 관계된 유전자의 19개의 SNP (ERCC1/2/4/5, XRCC1/2/4/5)를 조사하였다. 국내의 3개의 병원에서 169명의 만성기의 만성골수성백혈병 환자가 등록되었으며 DNA는 말초혈액을 채취하여 추출하였고, MALDI-TOF 방법으로 유전자형을 확인하였다. 결과: DNA를 복구경로에 관련된 후보(candidate) 단일염기다형성중, ERCC1 (rs11615) 와 ERCC5 (rs17655) 가 imatinib 치료반응과 유의한 연관성을 보여주었다. ERCC1 (rs11615) 의 TT 유전자형은 CC나 CT유전자형에 비하여 주요 세포유전학적 반응 (MCR)(p=0.015, HR 0.28 [95% C.I. [0.10-0.78]), 완전 세포유전학적 반응 (CCR)(p=0.021, HR 0.33 [95% C.I. 0.13-0.84]), 및 주요 분자적 반응 (MMR)(p=0.035, HR 0.36 [95% C.I. 0.14-0.93]) 을 달성할 확률이 높았으며, ERCC5 (rs17655) 의 CC나 CG유전자형은 GG유전자형 보다 imatinib 치료에 실패할 확율이 낮았다 (p=0.025 HR 2.52 [95% C.I. 1.12-5.67]). 결론: 본 연구결과는 뉴클레오티드 절단복구와 관련된 ERCC1이나 ERCC5의 단일염기다형성이 Imatinib 의 치료에 대한 반응을 예측할 수 있으며, imatinib 의 작용기전에 DNA 복구 기전이 연관되었을 가능성이 있음을 제시한다.