Genomic Characterization of Brain Metastasis in Non-Small Cell Lung Cancer Patients

摘要

Despite advances in systemic therapy, brain metastases remain a significant cause of mortality in non-small cell lung cancer (NSCLC) patients. We hypothesize that subpopulations of primary NSCLC tumor cells evolve through a multistep process of genomic and epigenomic alterations that result in a metastatic cell phenotype. In this proposal, we have utilized next generation exome sequencing to perform a comparative analysis of the genomes of patient- matched primary NSCLC and brain metastatic tumor cell populations. A population of 12 patients with NSCLC were used for a discovery set. We identified genomic alterations that were enriched in metastatic tumor cell populations and recurrent across patients. Several of these alterations (PIK3CA E535K, MAPK4 P246T) have been previously documented in NSCLC and are potential mediators of targeted therapeutics. One alteration (FES E651G) was correlated with time to brain metastatic recurrence in an independent set of primary NSCLC patients. This pilot data set demonstrate the validity and potential clinical utility of this experimental approach. Newly funded efforts are expanding these studies to larger patient populations, with the goal of identifying set of genomic alterations that define a gene network-based predictor of the brain metastatic phenotype in early stage NSCLC patients.