非小细胞肺癌ERBB家族基因突变分析与功能验证

Deregulated ERBB family genes including EGFR, HER2, ERBB3 and ERBB4 are the major targets for targeted therapies in malignant tumors. Although detection of oncogenic driver mutations are mainly limited to the kinase domains of EGFR and HER2 at present, the identification of oncogenic driver mutations in other sites of the ERBB family genes have continuously been reported in top journals recently. We sequenced the extracellular domain and transmembrane domain of EGFR, HER2 and ERBB3 in 120 lung adenocarcinomas which were “pan-negative” for well-identified driver mutations, and also found a series of important gene mutations, including oncogenic driver mutations of lung cancer as well as other malignant tumors. We plan to extend the mutational analysis by direct sequencing to 300 “pan-negative” lung adenocarcinoma samples out of about 2000 lung adenocarcinomas, and cover the full-length ERBB family genes excluding the kinase domains of EGFR and HER2. Functional analysis of the detected mutations will be performed to identify the novel oncogenic driver mutations. We will then carry out drug sensitive tests using a series of small molecule inhibitors which we already possess against certain oncogenic mutations. Finally, the clinicopathologic characteristics of the newly identified oncogenic driver mutations will be well defined in 3000 non-small cell lung cancers. Hopefully, our study can bring opportunities to receive targeted therapies to more Chinese lung cancer patients.

ERBB基因家族，包括EGFR、HER2、ERBB3和ERBB4基因的异常是恶性肿瘤靶向治疗的重要靶点。目前肺癌的致癌基因突变检测主要集中于EGFR和HER2的激酶域，但近年来国外权威期刊不断报道在ERBB家族基因的其它位点发现新的致癌基因突变。我们前期对120例常见致癌基因突变“全阴性”的肺腺癌进行EGFR、HER2、ERBB3胞外域和跨膜结构域的测序，也发现了一批重要基因突变，包括肺癌和其它恶性肿瘤中的致癌基因突变类型。我们计划在约2000例肺腺癌中选择300例“全阴性”的肺腺癌标本，对除EGFR和HER2的激酶域以外的ERBB基因家族全长进行突变检测，通过功能学实验验证其致癌性，并利用我们现有的分子靶向药物进行药敏实验，最后在3000例非小细胞肺癌中阐明新发现的致癌基因突变的临床病理特征。我们的研究有望为更多的中国肺癌患者带来接受靶向治疗的机会。

本研究旨在对中国非小细胞肺癌患者ERBB家族的致癌基因突变进行分析及功能验证。主要研究成果包括：（1）发现并通过功能学实验验证了ERBB基因家族全新的致癌基因突变——位于EGFR基因胞外域的EGFR M277E突变；（2）阐明中国非小细胞肺癌ERBB家族基因突变谱；（3）深入分析ERBB家族中的EGFR 18号外显子突变和HER2基因插入突变。我们的研究成果为我国肺癌患者带来了更多的潜在靶向治疗的机会。研究成果达到预期目标。