Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with Gefitinib
Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with Gefitinib
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DOI：
10.1016/j.lungcan.2008.12.025
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发表时间：
2009-10-01
期刊：
影响因子：
5.3
通讯作者：
Lin, Dongxin
中科院分区：
文献类型：
--
作者：
Ma, Fei;Sun, Tong;Lin, Dongxin
目的：EGFR的遗传变异可能改变蛋白质功能，从而改变表皮生长因子受体抑制剂的疗效。本研究探讨EGFR基因多态性与吉非替尼治疗晚期非小细胞肺癌（NSCLC）患者临床预后的关系。方法：采用全基因tag-SNP方法检测EGFR基因多态性。选择4个标签SNP，一个内含子1的CA简单序列重复（CA-SSR），一个编码区SNP（R521 K），以及EGFR酪氨酸激酶结构域中通过重测序鉴定的SNP，分析它们与84例接受吉非替尼治疗的晚期NSCLC患者的治疗结果和生存率的相关性。无进展生存率和总生存率采用考克斯模型调整临床因素后计算。结果：我们确定了两个EGFR基因多态性，rs 2293347（D994 D）和内含子1的CA-SSR，与吉非替尼治疗的临床结局相关。rs 2293347 GG或短CA重复基因型的有效率显著高于rs 2293347 GA或AA或长CA重复基因型（71.2%vs37.5%，P = 0.0043和88.5%vs48.3%，P = 0.0005）。与rs 2293347 GA或AA基因型相比，rs 2293347 GG基因型也与更长的无进展生存期相关（11个月vs 3个月，P = 0.0018）。结论：EGFR基因D994 D和CA-SSR多态性是吉非替尼治疗晚期非小细胞肺癌患者临床疗效的潜在预测因子。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Purpose: Genetic variations in EGFR may alter protein function and therefore the therapeutic efficacy of epidermal growth factor receptor inhibitors. This study investigated the association between polymorphisms in EGFR and clinical outcome in patients with advanced non-small-cell lung cancer (NSCLC) treated with Gefitinib.Methods: A whole gene-based tag-SNP approach was used to determine the candidate SNPs in EGFR. Four tag SNPs, one CA simple sequence repeat (CA-SSR) in intron 1, one coding region SNP (R521K), and SNPs identified by resequencing in the tyrosine kinase domain of EGFR were selected to analyze their association with therapeutic outcome and survival in 84 advanced NSCLC patients treated with Gefitinib. Progression-free and overall survivals were computed by Cox model adjusted for clinical factors.Results: We identified two EGFR polymorphisms, rs2293347 (D994D) and CA-SSR in intron 1, associated with clinical outcome of Gefitinib therapy. The response rate for the rs2293347GG or shorter CA repeat genotype was significantly higher than that for the rs2293347GA or AA or longer CA repeat genotype (71.2% versus 37.5%, P = 0.0043 and 88.5% versus 48.3%, P = 0.0005). The rs2293347GG genotype was also associated with longer progression-free survival compared with the rs2293347GA or AA genotype (11 months versus 3 months, P = 0.0018). A combination of rs2293347GG and shorter CA repeat genotypes had more pronounced clinical benefit.Conclusion: The D994D and CA-SSR polymorphisms in EGFR are potential predictors for clinical outcome in advanced NSCLC patients treated with Gefitinib. (C) 2009 Elsevier Ireland Ltd. All rights reserved.