中国非小细胞肺癌患者表皮生长因子受体突变的研究

Epidermal Growth Factor Receptor Mutation in Chinese Patients with Non-small Cell Lung Cancer

背景与目的:最近的研究结果表明,表皮生长因子受体(epidermalgrowthfactorreceptor,EGFR)基因酪氨酸激酶域的体细胞突变与非小细胞肺癌(non鄄smallcelllungcancer,NSCLC)患者对酪氨酸激酶抑制剂吉非替尼的敏感性密切相关。这些突变均发生在酪氨酸激酶域的ATP结合域附近,突变为19号外显子上的缺失突变,或18和21号外显子上的替代突变。研究发现,日本患者的突变率高于美国患者的突变率。本研究中我们分析中国NSCLC患者肺癌组织中EGFR突变情况。方法:收集2004年7月到10月间中山大学肿瘤防治中心52例可手术的NSCLC患者的新鲜组织标本,包括肿瘤组织标本和来自同一患者相应的正常肺组织标本。所有患者均未接受过吉非替尼治疗。采用PCR技术扩增EGFR基因的19和21号外显子,从正反两个方向对扩增片段进行DNA测序和分析。结果:52例1NNNSCLC患者中10例(19.2%)患者EGFR基因酪氨酸激酶域存在体细胞突变。10例突变中包括7例(70%)发生于19号外显子上的缺失突变,另外3例(30%)发生于21号外显子上的替代突变。腺癌(6/23,26.1%)、腺鳞癌(2/5,40.0%)和支气管肺泡癌(2/4,50.0%)的突变率高于鳞癌(0/20,0.0%)的突变率(P=0.025);非吸烟者的突变率(7/17,41.8%)高于吸烟者的突变率(3/35,8.6%)(P=0.009);而女性患者突变率(3/13,23.1%)与男性患者突变率(7/39,18.0%)无显著性差异(P=0.697)。结论:中国NSCLC患者EGFR的突变率较高,与日本患者的突变情况相似,明显高于高加索人种。

BACKGROUND ＆ OBJECTIVE： Recent studies showed that somatic mutations in epidermal growth factor receptor （EGFR） tyrosine kinase（TK） domain are associated with sensitivity of non-small cell lung cancer（NSCLC） to TK inhibitor gefitinib. The mutations, including in-frame deletions at exon 19 and substitutions at exon 18 or exon 21, cluster around ATP-binding pocket of TK domain. The frequence of mutations are higher in Japanese patients than in American patients. This study was to analyze EGFR mutations in Chinese patients with NSCLC. METHODS： From Jun. to Oct.2004, fresh specimens of lung cancer and corresponding normal lung tissue were collected from 52 consecutive NSCLC patients （39 men and 13 women）treated in Cancer Center of Sun Yat-sen University. All patients had not received treatment of gefitinib. DNA was extracted from the 52 specimens.Exons 19 and 21 were amplified by polymerase chain reaction （PCR）, and sequenced and analyzed from both sense and antisense directions.RESULTS： Somatic mutations in TK domain of EGFR in tumors were identified from 10 of the 52 （19.2%） patients, including 7 cases of in-frame deletion in exon 19 and 3 cases of amino acid substitution in exon 21, Mutation rate was significantly higher in adenocarcinoma, adeno-squamous carcinoma, and bronchioloalveolar cancer than in squamous cell carcinoma [26.1% （6/23）,40.0% （2/5）, and 50.0% （2/4） vs. 0 （0/20）, P=0.025], and significantly higher in non-smokers than in smokers [41.8% （7/17） vs. 8.6% （3/35）, P=0.009]. Mutation rate in women was similar to that in men [23,1% （3/13） vs,18.0% （7/39）, P=0.697]. CONCLUSION： EGFR mutation rate in Chinese NSCLC patients is similar to that in Japanese patients, and is obviously higher than that in Caucasian population.