Adenocarcinoma

Cancer

Lung

Gene

Biology

Internal medicine

Phenotype

Exome sequencing

Oncology

Brain metastasis

Genetics

Medicine

Metastasis

CDKN2A

Cancer research

Cancer Genetics

Brain metastases frequently arise from lung adenocarcinoma (BM-LUAD), yet the underlying genetic causes are poorly understood. In order to identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases, and we developed a Gaussian Process Latent Difference model for discovering candidate metastatic drivers under a case-control study design. Using this statistical model, 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, YAP1, and MMP13 and significantly more frequent deletions in CDKN2A/B. We confirmed that amplification frequencies of MYC and YAP1/MMP13 were elevated in an independent cohort of 105 patients. We further validated using patient-derived xenograft mouse models that MYC, YAP1 or MMP13 overexpression increased the incide...

53. Genomic characterization of brain metastases identifies drivers of metastatic lung adenocarcinoma