Ma Fei, Sun Tong, Shi Yuankai, Yu Dianke, Tan Wen, Yang Ming, Wu Chen, Chu Datong, Sun Yan, Xu Binghe, Lin Dongxin
Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Lung Cancer. 2009 Oct;66(1):114-9. doi: 10.1016/j.lungcan.2008.12.025. Epub 2009 Feb 6.
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.
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.
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.
The D994D and CA-SSR polymorphisms in EGFR are potential predictors for clinical outcome in advanced NSCLC patients treated with Gefitinib.
表皮生长因子受体（EGFR）的基因变异可能改变蛋白质功能，进而影响表皮生长因子受体抑制剂的治疗效果。本研究调查了EGFR基因多态性与接受吉非替尼治疗的晚期非小细胞肺癌（NSCLC）患者临床结局之间的关联。
采用基于全基因的标签单核苷酸多态性（tag-SNP）方法确定EGFR中的候选单核苷酸多态性。选择四个标签单核苷酸多态性、一个内含子1中的CA简单序列重复（CA-SSR）、一个编码区单核苷酸多态性（R521K）以及通过对EGFR酪氨酸激酶结构域进行重测序鉴定出的单核苷酸多态性，分析它们与84例接受吉非替尼治疗的晚期NSCLC患者治疗结局和生存的关联。无进展生存期和总生存期通过针对临床因素进行调整的Cox模型计算。
我们鉴定出两个与吉非替尼治疗临床结局相关的EGFR基因多态性，即rs2293347（D994D）和内含子1中的CA-SSR。rs2293347GG或较短CA重复基因型的缓解率显著高于rs2293347GA或AA或较长CA重复基因型（71.2%对37.5%，P = 0.0043；88.5%对48.3%，P = 0.0005）。与rs2293347GA或AA基因型相比，rs2293347GG基因型还与更长的无进展生存期相关（11个月对3个月，P = 0.0018）。rs2293347GG和较短CA重复基因型的组合具有更显著的临床益处。
EGFR中的D994D和CA-SSR基因多态性是接受吉非替尼治疗的晚期NSCLC患者临床结局的潜在预测指标。
