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.
The project addresses an important unmet need in the diagnosis and treatment of early stage lung cancer. Recent experience has shown that a large number of lung adenocarcinomas may be biologically and clinically indolent, and that other small early stage tumors may be biologically and clinically aggressive. Our project proposes to identify and validate specific genomic loci that are associated with biology that is indolent or aggressive. Our long term goal is to develop biomarkers that will stratify risk before or after resection of tumors that are similar radiographically or histologically, respectively.