Identification and Characterization of Gene Fusions in Lung Adenocarcinoma

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，肺腺癌代表了发病率不断增加的亚型。特异性改变的识别，如EGFR突变和最近的ALK激酶基因融合，已经导致肺腺癌患者含有这些改变的更有效的治疗。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R3HDM2-NFE2和最近的HSPA1A-NFKBIL1基因融合，并提名了许多其他潜在的基因融合候选基因。我们假设，在肺腺癌中鉴定新的基因融合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定标记提供新的途径。提出了三个具体目标。目的一是利用含有这些改变的肺癌细胞系中的siRNA敲除，以及利用经过改造过表达NFE2的肺细胞系，从功能上表征新型R3HDM2-NFE2基因融合。对肿瘤细胞增殖、侵袭和特定转录程序的影响将确定R3HDM2-NFE2致癌活性的机制。目的二是利用组织微阵列荧光原位杂交技术确定新型HSPA1A-NFKBIL1基因融合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，就像目的一中用于R3HDM2-NFE2的功能分析一样。目标三将采用用于发现R3HDM2-NFE2和HSPA1A- NFKBIL1融合的成功方法，以识别、验证和功能表征涉及肺癌中功能重要的细胞过程的其他新型融合。优先考虑作为靶向治疗候选的基因融合，或涉及可能开发治疗的基因和关键细胞靶点的基因融合。更高的重点也将放在候选发生在高频率或在可识别的肿瘤亚组。这些研究有可能找到治疗癌症死亡的主要原因的新方法。

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.