Lung Adenocarcinoma Invasion Genomics

描述（由申请人提供）：我们的项目重点是表征肺腺癌浸润获得的重要分子机制。我们的研究主要集中在描述侵袭的重要分子机制，这是转移的第一步。本小组和其他研究表明，早期肺腺癌患者的临床结果受组织学侵袭性的影响。随着我们看到肺癌的流行病学向早期，在某些情况下，尚未侵袭性疾病的转变，破译获得侵袭性的分子过程将变得越来越重要。提高对这些肿瘤生物学特性的了解，将加强早期肺癌的临床管理，包括指导小肺腺癌肿瘤的切除范围。我们的数据集丰富了早期非侵袭性腺癌（AIS，以前称为BAC）肿瘤，这些肿瘤在基因组库（如癌症基因组图谱（TCGA））中没有很好地代表。我们从肿瘤细胞中获得的初步基因表达谱结果表明，局灶性染色体拷贝数的增加在介导肺腺癌的侵袭获得中是重要的。这一创新发现是这个多学科、多机构项目的重点，旨在扩大我们对局灶体细胞拷贝数改变的基因组学研究，研究基质对侵袭的影响，研究基因扩增的诊断和治疗意义，并了解抑制AIS侵袭和促进腺癌侵袭的机制。利用特征良好的肺腺癌标本队列，我们将使用RNA和DNA微阵列、全外显子组测序和荧光原位杂交来验证具有拷贝数和mRNA水平综合改变的基因组位点对肺腺癌侵袭和转移能力的获得很重要的假设。在切除标本中验证后，这些基因座将在切除的肿瘤标本和早期肺腺癌肿瘤的细针抽吸中进行前瞻性临床试验。我们的长期目标是开发生物标志物，分别在放射学或组织学上均质肿瘤切除术前后对风险进行分层。

DESCRIPTION (provided by applicant): Our project focuses on characterizing the molecular mechanisms important for the acquisition of invasion in lung adenocarcinoma. Our research has focused on characterizing the molecular mechanisms important for invasion, the initial step of metastasis. Studies from our group and others indicate that clinical outcomes for patients with early stage lung adenocarcinoma are influenced by histological invasiveness. Deciphering the molecular processes underlying the acquisition of invasiveness promises to have increasing importance as we see a shift in the epidemiology of lung cancer towards early, and in some cases, not yet invasive disease. An improved understanding of the biological properties of these tumors will enhance the clinical management of early stage lung cancer, including directing the extent of resection for small lung adenocarcinoma tumors. Our dataset is enriched for early stage non-invasive adenocarcinoma (AIS, formerly called BAC) tumors that are not well represented in genomics repositories such as The Cancer Genome Atlas (TCGA). Our preliminary gene expression profiling results from tumor cells suggest that focal chromosomal copy number increase is important in mediating the acquisition of invasion in lung adenocarcinoma. This innovative discovery is the focus of this multidisciplinary, multi-institutional project to expand our genomics examination of focal somatic copy number alterations, examine the role of stromal influences on invasion, investigate the diagnostic and therapeutic implications of gene amplification, and to understand the mechanisms that repress invasion in AIS and promote invasion in adenocarcinoma. Using well characterized cohorts of lung adenocarcinoma specimens, we will use RNA and DNA microarrays, whole exome sequencing, and fluorescent in situ hybridization to test the hypothesis that genomic loci with integrated alterations of copy number and mRNA levels are important for the acquisition of invasion and metastasis capacity in lung adenocarcinoma. Upon validation in resected specimens, these loci will be brought forth for prospective clinical testing in resected tumor specimens and in fine needle aspirates acquired from early stage lung adenocarcinoma tumors. Our long term goal is to develop biomarkers that will stratify risk before or after resection of tumors that are homogenous radiographically or histologically, respectively.