Identification and Characterization of Gene Fusions in Lung Adenocarcinoma

肺腺癌基因融合的鉴定和表征

• 批准号: 8249361
• 负责人: DAVID George BEER
• 金额: $ 28.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249361
• 关键词: ALK gene; Address; Affect; Bioinformatics; Biological Assay; Biotechnology; Cancer Detection; Cancer Etiology; Cancer cell line; Cancerous; Categories; Cell Line; Cell Proliferation; Cell physiology; Cells; Cessation of life; Clinical; DNA Sequence Rearrangement; Data; Disease; Early Diagnosis; Engineering; Epidermal Growth Factor Receptor; Fluorescent in Situ Hybridization; Frequencies; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Fusion; Genes; Goals; Incidence; Lead; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Methodology; Monitor; Mutation; NF-kappa B; Nature; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Primary Neoplasm; Proteins; Research; Research Proposals; Role; Screening for cancer; Screening procedure; Signaling Pathway Gene; Small Interfering RNA; Specificity; Subgroup; Therapeutic; Tissue Microarray; Western Blotting; cancer cell; cancer therapy; cell growth; cellular targeting; fusion gene; innovation; member; mortality; neoplastic cell; new therapeutic target; next generation; novel; novel strategies; overexpression; programs; public health relevance; therapeutic target; tumor

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality worldwide with lung adenocarcinomas representing the subtype that is increasing in incidence. Identification of specific alterations such as EGFR mutations and more recently, ALK kinase gene fusions, have lead to the more efficacious treatment of patients whose lung adenocarcinomas contain these alterations. We have utilized a novel strategy for the identification of gene fusions in lung cancer (Wang et al, Nature Biotechnology) revealing the R3HDM2-NFE2 and more recently the HSPA1A-NFKBIL1 gene fusions in lung adenocarcinomas, as well as nominating many additional potential gene-fusion candidates. We hypothesize that identification of novel gene fusions in lung adenocarcinoma may provide new avenues for highly selective treatments of this cancer as well as specific markers for cancer detection or therapeutic monitoring. Three specific aims are proposed. Aim one is to functionally characterize the novel R3HDM2-NFE2 gene fusion utilizing siRNA knockdown in lung cancer lines containing these alterations as well as using lung cell lines engineered to overexpress NFE2. Effects on tumor cell proliferation, invasion and specific transcriptional programs will define the mechanisms underlying R3HDM2-NFE2 oncogenic activity. Aim two is to define the frequency of occurrence of the novel HSPA1A-NFKBIL1 gene fusion in primary lung cancers using fluorescence in situ hybridization with tissue microarrays, followed by functional analyses of the oncogenic activity of the fusion gene as those utilized for the R3HDM2-NFE2 in Aim one. Aim three will employ the successful methodologies used for the discovery of the R3HDM2-NFE2 and HSPA1A- NFKBIL1 fusions, to identify, validate and functionally characterize additional novel fusions involving functionally important cellular processes in lung cancer. Priority will be gene fusions that are candidates for targeted therapeutics or that involve genes and critical cellular targets for which therapies may be potentially developed. Higher emphasis will also be placed on candidates occurring at high frequency or within identifiable tumor subgroups. These studies have potential to identify new approaches to treat the leading cause of cancer death. PUBLIC HEALTH RELEVANCE: Lung cancer has the highest mortality of all cancers and best treated when detected early or with therapies directly against cancer-specific alterations. Gene fusions represent a new category of genetic alterations in lung cancer that can demonstrate this cancer-specificity and may be responsive to new therapies. This research proposal will identify new gene-fusions in lung cancer utilizing a newly developed bioinformatics approach combined with next-generation sequencing data. There is great potential that new therapeutic targets may be identified as well as markers for early detection that would directly impact survival of specific patients with lung cancer.

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，肺腺癌代表发病率增加的亚型。识别特定的改变，如EGFR突变，最近，ALK激酶基因融合，导致更有效的治疗患者的肺腺癌含有这些改变。我们利用了一种新的策略来鉴定肺癌中的基因融合（Wang等人，Nature Biotechnology），揭示了肺腺癌中的R3 HDM 2-NFE 2和最近的HSPA 1A-NFKBIL 1基因融合，并提名了许多其他潜在的基因融合候选者。我们推测，肺腺癌中新基因融合的鉴定可能为这种癌症的高选择性治疗以及癌症检测或治疗监测的特异性标志物提供新的途径。提出了三个具体目标。目的之一是在含有这些改变的肺癌细胞系中利用siRNA敲低以及使用经工程改造以过表达NFE 2的肺细胞系来功能性地表征新的R3 HDM 2-NFE 2基因融合体。对肿瘤细胞增殖、侵袭和特异性转录程序的影响将定义R3 HDM 2-NFE 2致癌活性的潜在机制。目的二是利用组织芯片荧光原位杂交技术确定新的HSPA 1A-NFKBIL 1融合基因在原发性肺癌中的发生频率，然后对融合基因的致癌活性进行功能分析，如目的一中用于R3 HDM 2-NFE 2的那些。目的三将采用用于发现R3 HDM 2-NFE 2和HSPA 1A-NFKBIL 1融合体的成功方法，以鉴定、验证和功能表征涉及肺癌中功能重要的细胞过程的另外的新融合体。优先考虑的基因融合是靶向治疗的候选者，或涉及基因和关键细胞靶点，可能会开发治疗方法。更高的重点也将放在候选人发生在高频率或可识别的肿瘤亚组。这些研究有可能确定治疗癌症死亡主要原因的新方法。 公共卫生关系：肺癌是所有癌症中死亡率最高的，最好的治疗方法是早期发现或直接针对癌症特异性改变的治疗。基因融合代表了肺癌中的一种新的遗传改变，可以证明这种癌症特异性，并可能对新疗法有反应。这项研究计划将利用新开发的生物信息学方法结合下一代测序数据来识别肺癌中的新基因融合。有很大的潜力，可以确定新的治疗靶点以及早期检测的标志物，这将直接影响特定肺癌患者的生存。