UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain; Department of Biochemistry, Faculty of Pharmacy, University of Granada Campus Universitario de Cartuja, s/n, 18071 Granada, Spain.
UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain.
Mutat Res Rev Mutat Res. 2017 Jan-Mar;771:32-58. doi: 10.1016/j.mrrev.2016.11.003. Epub 2016 Nov 23.
Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.
尽管基于铂类的化疗仍然是晚期 NSCLC 患者的标准治疗方法，但临床结果仍然不佳，大多数患者出现了高级别毒性。遗传因素，如参与铂类药物药效学、代谢和作用机制的单核苷酸多态性（SNPs），可能导致个体间在疗效和毒性方面存在差异。已经证明，参与 DNA 修复的基因以及 PI3K/PTEN/AKT 和 TGF-β 通路的其他基因的多态性与接受基于铂类化疗的晚期 NSCLC 患者的反应、生存和毒性相关。其他细胞过程，如 DNA 甲基化和增殖，通过叶酸代谢和细胞因子信号与铂类化疗方案的临床结果相关。在接受基于铂类化疗的晚期 NSCLC 患者中，对 NER 通路中基因多态性对临床结果的影响进行了广泛的研究，但报告的结果相互矛盾。最近和最全面的荟萃分析未能显示 ERCC1 C118T/C8092A 和 ERCC5 rs1047768 多态性与基于铂类化疗的反应之间存在关联。然而，其他 ERCC2（Lys751Gln 和 Asp312Asn）和 ERCC5（rs2094258 和 rs2296147）中的多态性分别与总生存期（OS）和无进展生存期（PFS）相关。XRCC1 中的 Arg194Trp 和 Gln399Arg 多态性也得到了广泛的研究。它们的影响似乎取决于种族，最近的荟萃分析证实了它们与亚洲患者而非高加索患者的反应相关。在 XRCC3 （DSB）修复途径中的 rs861539 多态性对总体缓解率（ORR）的影响也在一项荟萃分析中得到了证实。最后，编码 p53、PI3K、TGF-β、膜转运蛋白、谷胱甘肽代谢酶和细胞因子通路的蛋白质的基因中的 SNPs 得到了较少的研究。一些多态性已被报道与毒性或临床结果相关，但数据通常来自少数研究，需要进一步证实。
