肺腺癌新驱动突变基因IRS1的鉴定

With more than 1 million diagnoses and deaths per year, lung cancer represents the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer accounts for about 85% of all lung cancer cases, which can be further divided to lung adenocarcinoma, squamous cell lung cancer and large cell lung carcinoma. Lung adenocarcinoma is the most common subtype of lung cancer. More recently, these classifications have evolved to include molecular subsets based on targetable driver mutations, i.e., mutations which promote and sustain tumorigenesis. Lung cancers harboring specific driver mutations are sensitive to targeted drugs, which benefits lung cancer patients. Our previous study showed that 90% of lung adenocarcinoma patients from Chinese never smokers and 65% smoker patients harbored a driver mutation involving EGFR, HER2, ALK, KRAS, ROS1 or RET.All these known driver mutations have corresponding targeted drugs, some of them (Gefitinib, Erlotinib and Crizotinib) have shown significant benefit for patients harboring specific mutations. However, about 35%-50% of unselected lung adenocarcinomas from all comers (smokers and never smokers) do not harbor a known driver mutation. Thus far, we have identified IRS1, as new candidate driver mutations by whole exome sequencing and function prediction. In this study, we will further explore the phenotype,function and mechanism of this candidate driver mutation gene, including transformation ability, in vitro and in vivo tumor formation and proliferation, altered downstream pathways like MAPK and mTOR. Ultimately, this study will improve driver mutation spectrum and identify new potential targets for therapy in lung adenocarcinoma patients, which will finally benifit more lung adenocarcinoma patients.

肺癌是世界范围首位的癌症致死疾病，每年新发病例和死亡病例都超过100万，其中肺腺癌已经成为最常见的肺癌病例亚型。中国人群90%的不吸烟和65%的吸烟肺腺癌患者肿瘤有EGFR,HER2,ALK,KRAS,ROS1或RET驱动突变中的一种,这些突变都有对应的靶向药物，部分已经在临床上取得很好的疗效。但肺腺癌总体上有35%-50%的病例没有已知的驱动突变，这部分患者目前没有机会接受靶向治疗。在前期研究中，我们对18对没有已知驱动突变的肺腺癌样本进行全外显子组测序和功能预测，我们发现IRS1是一个全新的候选驱动突变基因。本课题将对IRS1基因突变进行表型、功能和机制的研究以鉴定其是否为肺腺癌驱动突变基因，包括突变的恶性转化能力，表达水平，体外体内成瘤和增殖能力的影响，对MAPK和mTOR信号通路的影响等。研究成果最终将完善肺腺癌驱动突变基因突变谱，促进新靶向药物药的开发，使更广泛的患者获益。

肺癌是世界范围排名首位的癌症致死疾病，最新的数据表明2012年世界范围内新发病例数为180万，占所有肿瘤死亡病例的13%。根据病理特点肺癌可以分为小细胞肺癌和非小细胞肺癌（NSCLC），后者又可进一步分为鳞癌，腺癌和大细胞癌，其中腺癌已经成为最常见的肺癌病例亚型。我们的前期研究发现在不吸烟的肺腺癌中90%的患者肿瘤有EGFR, HER2, ALK, KRAS 或 ROS1突变中的一种。但肺腺癌总体上有35%-50%的病例中没有已知的驱动突变，筛选和鉴定未知的驱动突变对新靶向药物的研发具有非常重要的意义。通过全外显子组测序对没有已知突变即“全阴性”样本进行检测，我们已经发现了IRS1是一个潜在的候选驱动突变基因。本课题对IRS1基因突变谱的扩大样本研究确认了该基因在肺腺癌中的体细胞突变，通过免疫组化的方法进行了组织芯片实验，证实了IRS1基因高表达的病例预后更差，无病生存（DFS）和总生存（OS）均少于低表达组。在功能学实验中我们发现虽然IRS1基因的表达水平未对肺腺癌细胞的增殖、和迁移产生明显影响，降低IRS1基因表达抑制了细胞克隆形成，IRS1基因的表达水平影响了细胞对化疗药物的反应。通过本课题的研究，我们证实了IRS1基因在肺腺癌中的突变和表达水平差异具有分子水平功能及临床意义，为进一步深入研究提供了依据。