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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]

PMID: 32203465

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Project description:BackgroundThe essential roles of the tumor microenvironment (TME) have been recognized during the initiation and progression of primary lung adenocarcinoma (LUAD). The aim of the present study was to delineate the immune landscape in both primary cancer and matched lymph node metastasis from a cohort of locally advanced stage LUAD patients with distinct outcomes.MethodsFormalin-fixed, paraffin-embedded samples were collected from 36 locally advanced LUAD patients. Transcriptome data of the tumor immune microenvironment were resolved using an immune oncology panel RNA sequencing platform. Bioinformatics approaches were used to determine the differentially expressed genes (DEGs), dysregulated pathways, and immune cell fraction between patients with early recurrence (ER) and late recurrence (LR).ResultsHere, we showed that in primary cancer tissues, 23 DEGs were obtained between patients with ER and LR. Functional analysis revealed that the LR in LUAD patients may be associated with enriched gene sets belonging to the antigen presentation and MHC protein complex, innate immune response, and IFN-γ signaling pathways. Next, the transcriptome data were adopted to quantify immune cell fractions, indicating that high infiltration of mast cells and neutrophils was correlated with ER. Interestingly, similar findings were observed in metastatic lymph nodes from patients suffering from ER or LR. By analyzing the shared immune features of primary cancers and lymphatic metastases, we unraveled the prognostic value and joint utility of two DEGs, CORO1A and S100A8.ConclusionsIn LUAD, the enrichment in antigen presentation, MHC protein complex, and IFN-γ signaling, and low infiltration of neutrophils in primary or metastatic nodules may be indications for a favorable prognosis. Integrated with bioinformatics approaches, transcriptome data of immune-related genes from formalin-fixed, paraffin-embedded (FFPE) samples can effectively profile the landscape of the tumor immune microenvironment and help predict clinical outcomes.

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

Publications

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

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