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


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.

SUBMITTER: Shih DJH 

PROVIDER: S-EPMC7136154 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Shih David J H DJH   Nayyar Naema N   Bihun Ivanna I   Dagogo-Jack Ibiayi I   Gill Corey M CM   Aquilanti Elisa E   Bertalan Mia M   Kaplan Alexander A   D'Andrea Megan R MR   Chukwueke Ugonma U   Ippen Franziska Maria FM   Alvarez-Breckenridge Christopher C   Camarda Nicholas D ND   Lastrapes Matthew M   McCabe Devin D   Kuter Ben B   Kaufman Benjamin B   Strickland Matthew R MR   Martinez-Gutierrez Juan Carlos JC   Nagabhushan Deepika D   De Sauvage Magali M   White Michael D MD   Castro Brandyn A BA   Hoang Kaitlin K   Kaneb Andrew A   Batchelor Emily D ED   Paek Sun Ha SH   Park Sun Hye SH   Martinez-Lage Maria M   Berghoff Anna S AS   Merrill Parker P   Gerstner Elizabeth R ER   Batchelor Tracy T TT   Frosch Matthew P MP   Frazier Ryan P RP   Borger Darrell R DR   Iafrate A John AJ   Johnson Bruce E BE   Santagata Sandro S   Preusser Matthias M   Cahill Daniel P DP   Carter Scott L SL   Brastianos Priscilla K PK  

Nature genetics 20200323 4


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  ...[more]

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