Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.

Brain metastases from lung adenocarcinoma (BM-LUAD) cause significant patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary lung adenocarcinomas. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12% vs 6%), YAP1 (7% vs 0.8%), and MMP13 (10% vs 0.6%) and significantly more frequent deletions in CDKN2A/B (27% vs 13%). We confirmed that amplification frequencies of MYC and YAP1 / MMP13 were elevated in an independent cohort of 105 patients. Functional assessment in patient-derived xenograft mouse models validated that MYC , YAP1 or MMP13 overexpression increased the brain metastasis incidence. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a large number of metastatic tumors can reveal novel metastatic drivers.