多种药物作用途径的遗传变异与化疗治疗晚期非小细胞肺癌患者的生存关系。
Genetic variations in multiple drug action pathways and survival in advanced stage non-small cell lung cancer treated with chemotherapy.
机构信息
Department of Health Sciences Research, Rochester, Minnesota, USA.
出版信息
Clin Cancer Res. 2011 Jun 1;17(11):3830-40. doi: 10.1158/1078-0432.CCR-10-2877.
PURPOSE
Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non-small cell lung cancer (NSCLC) treated with chemotherapy.
EXPERIMENTAL DESIGN
A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups.
RESULTS
A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20-1.77 and HR = 1.25; 95% CI = 1.05-1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11-1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50-0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38-0.77; HR = 0.67; 95% CI = 0.52-0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30-2.80; HR = 1.83; 95% CI = 1.27-2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis.
CONCLUSION
Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations.
目的
与抗癌药物生物活性相关的基因变异可能会影响治疗反应和肺癌预后。本研究系统研究了四个生物途径（谷胱甘肽代谢、DNA 修复、细胞周期和表皮生长因子受体（EGFR））中的遗传变异，以检验它们与接受化疗的晚期非小细胞肺癌（NSCLC）患者的生存情况之间的关联。
实验设计
在一个包含 1076 名患者的队列中，对来自四个途径的 70 个基因中的 894 个标记单核苷酸多态性（SNP）进行了基因分型和分析。在所有患者和主要化疗药物联合组中，在 SNP 和全基因水平上分析了与总生存的关系。
结果
在 GSS（谷胱甘肽途径）和 MAP3K1（EGFR 途径）存在遗传变异的患者中，总生存情况较差（HR=1.45；95%CI=1.20-1.77 和 HR=1.25；95%CI=1.05-1.50）。在接受铂类加紫杉烷治疗的患者的分层分析中，我们观察到 EGFR 途径中的 MAP3K1 变异（HR=1.38；95%CI=1.11-1.72）对总生存有危害作用，而 RAF1（HR=0.64；95%CI=0.50-0.82）对生存有保护作用。在接受铂类加吉西他滨治疗的患者中，RAF1 和 GPX5（谷胱甘肽途径）的遗传变异对生存有保护作用（HR=0.54；95%CI=0.38-0.77；HR=0.67；95%CI=0.52-0.85）；相反，NRAS（EGFR 途径）和 GPX7（谷胱甘肽途径）的变异对总生存有危害作用（HR=1.91；95%CI=1.30-2.80；HR=1.83；95%CI=1.27-2.63）。在全基因分析中，携带这些显著 SNP 的所有基因仍然具有显著性。
结论
晚期 NSCLC 患者接受铂类、紫杉烷和/或吉西他滨联合治疗时，EGFR 和谷胱甘肽途径基因的常见遗传变异可能与总生存相关。
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