Identification and characterization of driver gene(s) in recurrent lung cancer am

复发性肺癌驱动基因的鉴定和表征

• 批准号: 7380927
• 负责人: David Mu
• 金额: $ 28.79万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380927
• 关键词: 14q13; Address; Area; Biological Assay; Candidate Disease Gene; Clinical; Collaborations; DNA copy number; Data; Data Set; Diagnosis; Diagnostic; Epithelial Cells; Evaluation; Future; Gene Expression; Genes; Genome; Genomics; Gleevec; Goals; Growth; In Vitro; KRAS2 gene; Laboratories; Libraries; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Molecular; Numbers; Oligonucleotides; Oncogenes; Protein Overexpression; RNA Interference; RNA library; Range; Recurrence; Research; Research Personnel; Research Proposals; Resolution; Roche brand of trastuzumab; Sampling; Squamous cell carcinoma; Technology; Tumorigenicity; Work; base; cancer cell; design; follow-up; gain of function; gene function; in vivo; insight; loss of function; lung basal segment; lung carcinogenesis; novel; p21 K-Ras Protein; prognostic; success; therapeutic target; tool; transcription factor

DESCRIPTION (provided by applicant): We have completed analysis of over 250 lung cancer samples by a high- resolution genome profiling method developed here at Cold Spring Harbor Laboratory (CSHL). We found twelve major recurrent amplicons, most of which contain known driver genes such as MYC or KRAS2, and three others that do not, including the second most frequent amplicon which is located at 14q13. Our first specific aim is to perform comprehensive functional evaluation of all three candidate driver genes within this frequently amplified region at 14q13. This comprehensive functional evaluation will utilize both gain-of-function transformation assays and loss-of-function assays using new RNA interference technology, developed here at CSHL, that silences gene expression in vitro and in vivo. We have preliminary data that indicates that all three genes, each encoding a different transcription factors, synergistically promote the proliferation of lung epithelial cells. In addition to functional analysis, we have formed collaborations to address the potential diagnostic and prognostic significance of 14q13 amplification. The other two novel frequent amplicons contain several candidate genes. To address the difficulty inherent in functional analysis of amplicons containing many overexpressed genes, our second specific aim is to develop new barcoded RNA library interference technology, which enables functional analysis of many genes in parallel, into a robust tool for functional analysis of amplicons with large numbers of candidate driver genes. Our results will produce new insights into the molecular basis of lung carcinogenesis and should identify key therapeutic targets and new strategies for diagnostics for this highly lethal cancer. The first goal of this study focuses on the discovery and functional characterization of novel causal genes of one of the most deadly forms of lung cancer. The second goal is to create a gene function-based tool to enable researchers to rapidly identify the causal gene within a recurrent amplified genomic region that contains too many genes to be studied by a gene-by-gene approach. Forward research progress of this research proposal is expected to positively impact the diagnosis and treatment of lung cancer in the future.

描述（由申请人提供）：我们通过在冷泉港实验室（CSHL）开发的高分辨率基因组分析方法（CSHL）完成了250多种肺癌样本的分析。我们发现了十二个主要的复发扩增子，其中大多数包含已知的驱动基因，例如MYC或KRAS2，还有三个没有的驱动基因，包括位于14q13的第二频繁频繁的扩增子。我们的第一个具体目的是在2013年第14季度经常放大区域内对所有三个候选驱动器基因进行全面的功能评估。这种全面的功能评估将利用功能获得的转换测定法和使用新的RNA干扰技术的功能丧失测定，该技术在CSHL上开发，在体外和体内沉默了基因表达。我们有初步数据，表明所有三个基因（每个基因都编码不同的转录因子）协同促进肺上皮细胞的增殖。除了功能分析外，我们还成立了协作，以解决14Q13扩增的潜在诊断和预后意义。其他两个新型频繁的扩增子包含几个候选基因。为了解决包含许多过表达基因的扩增子的功能分析固有的困难，我们的第二个特定目的是开发新的条形码RNA库干涉技术，该技术可以将许多基因的功能分析成为可稳健的工具，用于对具有大量候选驱动器基因的扩增子的功能分析。我们的结果将对肺癌发生的分子基础产生新的见解，并应确定这种高度致命癌症的诊断剂的关键治疗靶标和新策略。这项研究的第一个目标集中于最致命形式的肺癌之一的新因果基因的发现和功能表征。第二个目标是创建一个基于基因功能的工具，以使研究人员能够在复发的放大基因组区域内迅速识别因子基因过多而无法通过基因方法研究的基因。预计将来该研究建议的远期研究进度将对肺癌的诊断和治疗产生积极影响。