Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov sq., 2, Moscow, Russia.
Pharmacogenomics. 2014 Feb;15(3):329-37. doi: 10.2217/pgs.13.237.
Cisplatin and its analogs are potent antitumor agents. However, their use is restricted by significant variability in tumor response and toxicity. There is a great need to identify genetic markers to predict the most important adverse events and patient outcomes.
MATERIALS & METHODS: We have evaluated the association between polymorphisms in 106 genes involved mainly in xenobiotic metabolism, DNA repair, the cell cycle and apoptosis, and outcomes in 104 ovarian cancer patients receiving cisplatin-cyclophosphamide chemotherapy. Arrayed primer extension technology was used to genotype 228 SNPs.
Ten SNPs in nine genes were found to be associated with one or more of the assessed clinical end points. SNPs in TPMT and NQO1 were significantly associated with progression-free survival. Polymorphisms in ERCC5, RAD52, MUTYH and LIG3 correlated with the occurrence of severe neutropenia. SNPs in NAT2 and EPHX1 were associated with anemia and nephrotoxicity, respectively. A SNP in ADH1C was correlated with complete tumor response.
The results obtained suggest that SNPs in different genes involved in drug metabolism can be important in identifying patients at risk for nonresponse to or toxicity from cisplatin-based treatment.
顺铂及其类似物是有效的抗肿瘤药物。然而，由于肿瘤反应和毒性的显著差异，它们的应用受到限制。非常有必要确定遗传标志物，以预测最重要的不良事件和患者结局。
我们评估了 106 个主要参与外源物代谢、DNA 修复、细胞周期和凋亡的基因中的多态性与 104 例接受顺铂-环磷酰胺化疗的卵巢癌患者结局之间的关系。使用引物延伸阵列技术对 228 个 SNP 进行基因分型。
在 9 个基因中的 10 个 SNP 与评估的临床终点之一或多个相关。TPMT 和 NQO1 中的 SNP 与无进展生存期显著相关。ERCC5、RAD52、MUTYH 和 LIG3 中的多态性与严重中性粒细胞减少的发生相关。NAT2 和 EPHX1 中的 SNP 分别与贫血和肾毒性相关。ADH1C 中的 SNP 与完全肿瘤反应相关。
这些结果表明，不同基因中参与药物代谢的 SNP 可能是识别对顺铂治疗无反应或毒性风险患者的重要因素。
