Project Summary Fifty percent of patients with lung adenocarcinoma will develop brain metastases. Patients frequently develop brain metastasis even while their extracranial disease remains under control. Unfortunately, treatment options are limited, and most current clinical trials in the US exclude patients with brain metastases. Our limited understanding of the molecular drivers of brain metastases has hampered the development of novel therapeutics for this common complication of cancer. Our group recently completed whole-exome sequencing of 104 brain metastases, primary tumors and normal tissue across many histologies. In this initial dataset, which included only 29 brain metastases from lung adenocarcinoma, we detected clinically actionable alterations that were unique to the brain metastases. We have now assembled a large cohort of lung adenocarcinoma brain metastases. Our proposed genomic analysis will focus on identifying and characterizing the molecular alterations in brain metastases from lung adenocarcinoma. We will analyze brain metastases and primary lung tumors and compare to lung cancers that do not metastasize. We will characterize these alterations using in vitro and in vivo assays of metastasis, including patient derived xenograft models. Identification of these mutations will aid in the design of more effective treatments for brain metastases.