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 polimorfisms (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 5 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 11 g/dl (Odds ratio [OR] 5 5.0, 95% confidence interval [CI] 5 1.5-16.1) or a non-CA XPC haplotype (OR 5 4.1, 95% CI 5 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. Am. J. Hematol. 85:482-486, 2010. V

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…101 In addition, DNA ligase I, a ligase involved in nucleotide excision repair and base excision repair, has recently been implicated in backup NHEJ, where it was associated with promoting chromosomal translocations. 102 Moreover, singlenucleotide polymorphisms in the DNA ligase I gene were found in patients with chronic myeloid leukaemia 103 and some mutations are connected to increased risk of lung cancer. 104 So far, no human cancer has been associated with XLF mutations.…”

Prediction of personalized drugs based on genetic variations provided by DNA sequencing technologies

“…In contrast, the mutant TT homozygotes or CT heterozygotes in XPC499 had an increased likelihood of nonresponders compared to the wild-type CC homozygotes. No significant difference was observed for other SNPs (Guillem et al, 2010).…”

“…Several reports recently demonstrated the association between SNPs and the responses to gene therapy (Table 3). The response to imatinib treatment in patients with chronic myeloid leukemia (CML), as a good example for this approach, has been performed (Guillem et al, 2010). Imatinib, which is a remarkably effective drug for CML that results from the clonal expansion of pluripotent hematopoietic stem cells containing the BCR-ABL fusion gene, permits long-term disease control in about three fourths of patients, but some patient do not respond to the treatment (Druker et al, 2006).…”

DNA repair mechanisms protect our genome from carcinogenesis

“…It has been shown that the assessment of DNA repair characteristics can be very informative in the choice and prediction of the outcome of therapy, even though further studies with a larger number of patients are often required for confirmation of results. Polymorphisms in the NER genes XPG and XPC, for instance, are associated with the differential response of chronic myeloid leukemia patients to treatment with imatinib (170). The A23G polymorphism of the NER gene XPA is associated with increased response of non-small cell lung cancer patients to platinum-based chemotherapy (171).…”