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.
We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.
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