摘要
目的：针对EGFR的靶向治疗成为继手术、放疗和化疗后NSCLC治疗的又一重要手段，但EGFR特异性抑制剂gefitinib对NSCLC的有效率远低于EGFR在NSCLC中的表达率，并且有证据表明gefitinib疗效与肿瘤细胞的EGFR表达水平无关。NSCLC EGFR酪氨酸激酶结构域突变的发现揭示了肺癌对gefitinib敏感的分子机制，并为预测gefitinib疗效提供了极佳的预测指标。在Ⅱ期临床试验IDEAL1中，日本患者的有效率高于白种人，与此对应的是，日本NSCLC患者中EGFR酪氨酸激酶结构域的突变率高于美国NSCLC患者，提示EGFR突变存在人种间差异。gefitinib在中国NSCLC患者中同样有较高有效率，但目前尚无关于中国NSCLC中EGFR突变情况的报道。本研究旨在对EGFR在中国NSCLC患者中的突变情况进行分析，并进一步验证EGFR酪氨酸激酶结构域突变与gefitinib疗效间的相关性。
方法：原发NSCLC组织标本取自76例中国患者，其中54例患者未接受gefitinib治疗，22例为gefitinib治疗的患者；所用的肿瘤标本均取自患者进行系统治疗前。用PCR方法对EGFR18～21外显子进行扩增，PCR产物直接测序，所有类型突变均经克隆测序进一步确证。
结果：28例标本中检测到29个突变(不包括2种沉默突变)，包括15个缺失突变和14个错义突变。根据突变引起氨基酸序列的改变，突变分为8种：6种类型的缺失突变均位于19外显子，包括3种单纯的缺失突变(delE746-A750；delL747-P753insS；delE746-T751insA)，3种缺失突变合并错义突变(delL747-E749，A750P，T751I；delL747-A750，T751P；delL747-S752，P753Q)；另2种类型的突变为位于21外显子的L858R和L861Q。2种沉默(2361G＞A，Q787Q；2316C＞T，P772P)突变均位于20外显子。在gefitinib治疗的22例患者中，7例疗效为PR患者的肿瘤标本均有突变，8例疗效为PD的患者均无突变(P＜0.001)；7例SD的患者中3例突变，如果用疾病控制率(disease control rate，DCR，
Objective: Therapy targeted EGFR has become another important modality for treatment NSCLC following surgery, radiotherapy and chemotherapy. But rate of tumor response to gefitinib, a specific EGFR tyrosine kinase inhibitor, was much lower than that of NSCLC with EGFR over-expression, and it has been demonstrated that the level of EGFR expression was not associated with tumor response. The discovery of mutations in EGFR tyrosine kinase domain revealed the mechanism mediating tumor response to gefitinib, and provided a powerful predictor for gefitinib therapy. In phase II clinical trial, tumor response to gefitinib was found more frequently in Japanese NSCLCs. Correspondingly, higher incidence of EGFR mutation was observed in NSCLC patients of Japanese origin compared with those of American origin, indicating different frequency of such mutation between different ethnics. Higher rate of tumor response to gefitinib was also found in Chinese NSCLCs, however, no data about such mutations in Chinese patients with NSCLC could be obtained. In the study we aimed to screen such mutations in Chinese NSCLCs and confirm the correlation between EGFR mutation and tumor response to gefitinib.
Methods: Primary NSCLC tissues were obtained for analysis of mutations in exons 18-21 of EGFR from a total of 76 Chinese patients, of whom 54 did not receive gefitinib therapy and 22 did. All tumor tissues were obtained during diagnosis or surgical procedure before any treatment of lung cancer. PCR products were sequenced directly and mutations were confirmed by an independent PCR and sequence. All types of mutation were cloned and sequenced.
Results: 29 mutations were found in 28 tumor tissues not including 2 types of silent mutation, in which included 15 deletion mutations and 14 missense mutations. All mutations can be divided into 8 types, in which 6 types of mutation were occurred in exon 19, 2 types of mutation (L858R and L861Q)were observed in exon 21. Among 6 types of deletion, 3 were simple deletions (delE746-A750; delL747-P753insS; del E746-T751insA), other 3 were deletions coupled with point mutations (delL747-E749, A750P, T751I; delL747-A750, T751P; delL747-S752, P753Q). 2 types of silent mutation (2361G>A, Q787Q; 2316C>T, P772P) were detected in exon 20.
引文
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