Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma

Nat Genet. 2020 Apr;52(4):371-377. doi: 10.1038/s41588-020-0592-7. Epub 2020 Mar 23.

Abstract

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause 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 LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Case-Control Studies
  • Cell Line
  • DNA Copy Number Variations / genetics
  • Female
  • Genes, myc / genetics
  • Genomics / methods
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • Mice
  • Mice, Nude
  • Mutation / genetics
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Transcription Factors / genetics
  • Whole Exome Sequencing

Substances

  • Transcription Factors
  • Matrix Metalloproteinase 13