驱动实体亚型肺腺癌基因异常筛选和鉴定研究

Lung cancer was the leading cause of cancer-related mortality worldwide and lung adenocarcinoma is its most common histologic type. More recently, a new histologic classification system for lung adenocarcinoma was proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS), based on the semiquantitative identification of the predominant histologic subtype. The IASLC/ATS/ERS classification system is independently associated with overall survival and disease recurrence in adenocarcinomas. Subtypes with solid predominant growth patterns have more aggressive biological behavior than other subtypes. We previously showed that solid growth pattern adenocarcinoma is associated with early recurrence. Identification of the genetic alterations driven this subtype of cancer would provide clinical benefits for patients with lung cancer. Considering the large number of lung cancer cases, the number of patients who have solid component in their tumor is enormous. .In current study, we performed whole-exome sequencing from 30 pure solid lung adenocarcinomas samples from tumor and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were also conducted for a subset of these samples. Clinical association with solid adenocarcinoma specific somatic alterations was investigated. Then, we will characterize the solid adenocarcinoma specific somatic alterations of intratumor heterogeneity using immunohistochemical analysis, Sanger sequencing and FISH. Functional and mechanical investigation of these candidate genetic alterations driven solid adenocarcinoma would be also performed. In addition, we will also uncover the association of solid adenocarcinoma specific genetic alterations with chemotherapy and targeted drugs. This analysis will result in the characterization of the genetic alterations acting in solid growth pattern lung adenocarcinomas and identify the potential therapeutic targets.

肺腺癌是肺癌中最常见的病理类型。根据最新腺癌分型系统，肺腺癌可进一步分为腺泡、贴壁、乳头、微乳头、实体及黏液腺癌等病理亚型。其中实体亚型腺癌侵袭性强，容易复发和转移，患者预后极差。阐明实体亚型肺腺癌发生分子机制对预测这种高侵袭性腺癌及开发针对性靶向药物具有重要临床意义。本研究拟汇集本研究中心及国际已发表大规模测序信息，筛选出驱动实体亚型腺癌发生的可能分子异常。进一步通过显微微切割技术在1000例肺腺癌中验证，挑选出与实体亚型腺癌发生有关的候选基因。接着通过CRISPR-Cas9基因编辑技术通过体内及体外实验阐明候选基因在实体亚型腺癌组织形成中作用与机制。最后分析这些基因异常对各种靶向药物疗效的影响。研究结果将极大加深我们对实体亚型腺癌发生机制的了解，同时将推进靶向药物的开发及相应临床试验的开展。

实体亚型腺癌侵袭性强，容易复发和转移，患者预后极差。阐明实体亚型肺腺癌发生分子机制对预测这种高侵袭性腺癌及开发针对性靶向药物具有重要临床意义。本研究汇集本研究中心及国际已发表大规模测序信息，筛选出NF1, SETD2, MET, EGFR突变或扩增，可能从参与了实体亚型腺癌发生。通过CRISPR-Cas9基因编辑技术通过体内及体外实验阐明了MET基因在实体亚型腺癌组织形成中作用与机制。最后还分析其与EGFR协同致癌，靶向EGFR能抑制met突变肿瘤的生长。研究结果对推进临床靶向药物指征扩大及相应临床试验的开展具有重要意义。