Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma
| Autor: | Scott L. Carter, Juan Carlos Martinez-Gutierrez, Tracy T. Batchelor, Ibiayi Dagogo-Jack, Christopher Alvarez-Breckenridge, Priscilla K. Brastianos, Sun Ha Paek, Michael White, Benjamin Kaufman, Kaitlin Hoang, Nicholas D. Camarda, Daniel P. Cahill, Megan R. D'Andrea, Anna S. Berghoff, Mia Bertalan, Parker H. Merrill, Darrell R. Borger, Sun Hye Park, Devin McCabe, Sandro Santagata, Deepika Nagabhushan, Franziska M. Ippen, A. John Iafrate, Matthew R. Strickland, Ryan P. Frazier, Naema Nayyar, Matthew Lastrapes, Ivanna Bihun, Emily Batchelor, Elisa Aquilanti, Maria Martinez-Lage, Brandyn A. Castro, Ben Kuter, Matthias Preusser, Matthew P. Frosch, Magali De Sauvage, David Shih, Andrew Kaneb, Bruce E. Johnson, Alexander Kaplan, Ugonma Chukwueke, Elizabeth R. Gerstner, Corey M. Gill |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Lung Neoplasms DNA Copy Number Variations Somatic cell Genes myc Mice Nude Adenocarcinoma of Lung Biology Cell Line Mice 03 medical and health sciences 0302 clinical medicine CDKN2A Matrix Metalloproteinase 13 Exome Sequencing Genetics medicine Animals Humans Neoplasm Metastasis Exome sequencing 030304 developmental biology 0303 health sciences Lung Brain Neoplasms Case-control study Genomics Human brain medicine.disease 3. Good health HEK293 Cells medicine.anatomical_structure Case-Control Studies Mutation Cancer research Adenocarcinoma Female 030217 neurology & neurosurgery Transcription Factors Brain metastasis |
| Zdroj: | Nature Genetics. 52:371-377 |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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