Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
J Thorac Oncol. 2012 Oct;7(10):1609-17. doi: 10.1097/JTO.0b013e3182653d31.
Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy.
In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model.
There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p < 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A>C, XRCC3 -316A>G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity.
Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.
影响 DNA 修复能力的遗传多态性可以调节细胞毒性药物的疗效和毒性。因此，我们的研究目的是评估 DNA 修复基因中遗传变异对接受吉西他滨-铂类联合化疗的恶性间皮瘤（MM）患者治疗结果的影响。
总共对 109 例 MM 患者的 XRCC1、NBN、RAD51 和 XRCC3 基因中的 10 个多态性进行了基因分型。通过逻辑回归分析确定所选多态性对肿瘤反应和治疗相关毒性发生的影响，通过 Cox 比例风险模型估计其对生存的影响。
在所研究的多态性与肿瘤反应之间没有关联，但我们观察到 XRCC1 399Gln 等位基因与总生存期降低之间存在显著关联（风险比=1.70；95%置信区间[CI]1.06-2.73；p=0.028）。XRCC1 399Gln 等位基因与 C 反应蛋白水平之间的相互作用表明，至少携带一个 XRCC1 399Gln 等位基因且 C 反应蛋白水平高于中位数的患者总生存时间明显短于其他患者（12.9 个月与 25.3 个月，对数秩检验 p<0.001）。我们还观察到 XRCC1 399Gln 与白细胞减少症（比值比[OR]=0.25；95%CI0.09-0.67；p=0.006）、中性粒细胞减少症（OR=0.24；95%CI0.09-0.68；p=0.007）和血小板减少症（OR=0.27；95%CI0.09-0.84；p=0.024）的较低频率之间存在关联。此外，NBN 3474A>C、XRCC3-316A>G 和 Thr241Met 多态性与治疗相关毒性显著相关。
我们的结果支持 DNA 修复基因多态性，特别是 XRCC1 Arg399Gln 多态性，可能改变吉西他滨-铂类联合化疗反应的假设，并且首次在 MM 患者中显示出这种作用。
