title: XPC genetic polymorphisms correlate with the response to imatinib treatment in patients with chronic phase chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is driven by the BCR-ABL protein, which promotes the proliferation and viability of the leukemic cells. Moreover, BCR-ABL induces genomic instability that can contribute to the emergence of resistant clones to the ABL kinase inhibitors. It is currently unknown whether the inherited individual capability to repair DNA damage could affect the treatment results. To address this, a comprehensive analysis of single nucleotide polymorphisms (SNPs) on the nucleotide excision repair (NER) genes (ERCC2-ERCC8, RPA1-RPA3, LIG1, RAD23B, XPA, XPC) was performed in 92 chronic phase CML patients treated with imatinib upfront. ERCC5 and XPC SNPs correlated with the response to imatinib. Haplotype analysis of XPC showed that the wild-type haplotype (499C-939A) was associated with a better response to imatinib. Moreover, the 5-year failure free survival for CA carriers was significantly better than that of the non-CA carriers (98% vs. 73%; P = 0.02). In the multivariate logistic model with genetic data and clinical covariates, the hemoglobin (Hb) level and the XPC haplotype were independently associated with the treatment response, with patients having a Hb < or =11 g/dl (Odds ratio [OR] = 5.0, 95% confidence interval [CI] = 1.5-16.1) or a non-CA XPC haplotype (OR = 4.1, 95% CI = 1.6-10.6) being at higher risk of suboptimal response/treatment failure. Our findings suggest that genetic polymorphisms in the NER pathway may influence the results to imatinib treatment in CML.
authors.affiliation: Hematology and Medical Oncology Department, Hospital Clínico Universitario, Avd. Blasco Ibáñez 17, Valencia, Spain.
authors.forename: Vicent M
authors.initials: VM
authors.lastname: Guillem
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: Jesús
authors.initials: J
authors.lastname: Martínez
authors.forename: Alberto
authors.initials: A
authors.lastname: Alvarez-Larrán
authors.forename: María
authors.initials: M
authors.lastname: Collado
authors.forename: Mireia
authors.initials: M
authors.lastname: Camós
authors.forename: Anna
authors.initials: A
authors.lastname: Sureda
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffioli
authors.forename: Isabel
authors.initials: I
authors.lastname: Marugán
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Hernández-Boluda
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D010879:Piperazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D004720:Endonucleases; D006454:Hemoglobins; D000068877:Imatinib Mesylate; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C086984:XPC protein, human