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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 genomic features of cancer cells may confer the metastatic ability of lung adenocarcinoma (LUAD) to metastasize to specific organs. We aimed to identify the differences in genomic alterations between patients with primary LUAD with and without metastases and to elucidate the metastatic biology that may help developing biomarker-directed therapies for advanced or metastatic disease.MethodsA retrospective cohort of 497 patients with LUAD including 388 primary tumors (PR), 53 bone metastases (MT-bone), 30 liver metastases (MT-liver), and 26 brain metastases (MT-brain) was tested for genomic alterations by a next-generation sequencing assay.ResultsThe EGFR, TP53, TERT, LRP1B, CDKN2A, ERBB2, ALK, and KMT2C genes had a high frequency of mutations, and the mutations were shared by PR and metastases groups. TP53 and EGFR were the most common mutated genes. In comparison with PR, KRAS, STK11, ATM, NPM1, and ROS1 were significantly mutated in MT-brain, and TP53, MYC, RSPO2, CDKN2a, and CDKN2B were significantly mutated in MT-liver. The frequencies of TP53, CDKN2A, MTAP, PRKCI, and APC mutations were higher in MT-bone than that in PR. The ERBB, phosphoinositide-3-kinase/protein kinase B (PI3K-AKT), cell cycle, Fibroblast growth factor (FGF), and homologous recombination deficiency signaling pathways were affected in both PR and metastases, and there is higher frequency of mutations in metastases. Moreover, the co-mutations in patients with PR and metastasis were respectively analyzed. In addition, the programmed death ligand 1 (PD-L1) level was obviously related to tumor stage and tumor metastases, and the tumor mutational burden was correlated to clinicopathological features including age, gender, pathological stages, and tumor metastases. FGFR1, KAT6A, MYC, RAD21, TP53, and DAXX were also dramatically correlated to the tumor mutational burden.ConclusionMetastases are the most devastating stage of tumors and the main cause of cancer-related deaths. Our results provided a clinically relevant view of the tumor-intrinsic mutational landscape of patients with metastatic LUAD.

Project description:BackgroundBrain metastases are associated with considerable negative effects on patients' outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases.Materials and methodsProteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259.ResultsOut of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. Pathways associated with the immune system, cell-cell/matrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases.ConclusionsThis is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.

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

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

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