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BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS

BACKGROUND: Adenocarcinomas (ADC) are the most common lung tumours and EGFR-mutant lesions have a higher risk of brain metastasis development, which confers poorer survival. Genetic and epigenetic signatures of brain metastasis have not been comprehensively identified. The aim of this study is to co...

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Autores principales: Mamatjan, Yasin, Zuccato, Jeffrey, Karimi, Shirin, Cabanero, Michael, Weiss, Jessica, Sorotsky, Hadas, Tsao, Ming, Shepherd, Frances, Aldape, Kenneth, Zadeh, Gelareh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213095/
http://dx.doi.org/10.1093/noajnl/vdz014.022
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author Mamatjan, Yasin
Zuccato, Jeffrey
Karimi, Shirin
Cabanero, Michael
Weiss, Jessica
Sorotsky, Hadas
Tsao, Ming
Shepherd, Frances
Aldape, Kenneth
Zadeh, Gelareh
author_facet Mamatjan, Yasin
Zuccato, Jeffrey
Karimi, Shirin
Cabanero, Michael
Weiss, Jessica
Sorotsky, Hadas
Tsao, Ming
Shepherd, Frances
Aldape, Kenneth
Zadeh, Gelareh
author_sort Mamatjan, Yasin
collection PubMed
description BACKGROUND: Adenocarcinomas (ADC) are the most common lung tumours and EGFR-mutant lesions have a higher risk of brain metastasis development, which confers poorer survival. Genetic and epigenetic signatures of brain metastasis have not been comprehensively identified. The aim of this study is to compare the methylome of EGFR-mutant primary lung tumor and matched brain metastasis to identify mechanisms of brain metastasis and new treatment targets. METHOD: Seven matched primary to brain metastasis tumours were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Hierarchical clustering and principal component analyses (PCA) were performed using most variable CpG sites. Supervised analyses were performed between lung and brain tumour samples. Copy number variation (CNV) plots identified alterations between pairs along with Leukocytes unmethylation for purity (LUMP) score and prediction lymphocyte proportion analyses to measure immune infiltration. RESULTS: Unsupervised clustering showed that the fourteen tumours clustered according to patient with similar methylation profiles between each of seven matched pairs. On the supervised analysis using 83K significant CpG sites, the fourteen samples clustered into two groups based on tumour site being lung or brain. Of these 83K CpG sites, 2.4K were either hypermethylated or hypomethylated in all lung samples. One quarter of these 2.4K CpG sites were located in promoter regions. CNV analyses showed losses of FGFR1, C19MC, CDKN2A, PTCH1, and MYCN genes with higher deep deletions in brain versus lung primary samples. Immune infiltration measures were similar between lung and brain metastasis pairs (LUMP-score=0.64) consistent with high immune cell infiltration. CONCLUSION: In this EGFR-mutant lung adenocarcinomas and matched brain metastases, differentially methylated CpG sites and CNV alterations are identified that distinguish lung from brain samples. Further work with additional matched samples may further elucidate signatures specific to brain metastasis and aid in our understanding of the mechanisms of brain metastasis.
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spelling pubmed-72130952020-07-07 BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS Mamatjan, Yasin Zuccato, Jeffrey Karimi, Shirin Cabanero, Michael Weiss, Jessica Sorotsky, Hadas Tsao, Ming Shepherd, Frances Aldape, Kenneth Zadeh, Gelareh Neurooncol Adv Abstracts BACKGROUND: Adenocarcinomas (ADC) are the most common lung tumours and EGFR-mutant lesions have a higher risk of brain metastasis development, which confers poorer survival. Genetic and epigenetic signatures of brain metastasis have not been comprehensively identified. The aim of this study is to compare the methylome of EGFR-mutant primary lung tumor and matched brain metastasis to identify mechanisms of brain metastasis and new treatment targets. METHOD: Seven matched primary to brain metastasis tumours were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Hierarchical clustering and principal component analyses (PCA) were performed using most variable CpG sites. Supervised analyses were performed between lung and brain tumour samples. Copy number variation (CNV) plots identified alterations between pairs along with Leukocytes unmethylation for purity (LUMP) score and prediction lymphocyte proportion analyses to measure immune infiltration. RESULTS: Unsupervised clustering showed that the fourteen tumours clustered according to patient with similar methylation profiles between each of seven matched pairs. On the supervised analysis using 83K significant CpG sites, the fourteen samples clustered into two groups based on tumour site being lung or brain. Of these 83K CpG sites, 2.4K were either hypermethylated or hypomethylated in all lung samples. One quarter of these 2.4K CpG sites were located in promoter regions. CNV analyses showed losses of FGFR1, C19MC, CDKN2A, PTCH1, and MYCN genes with higher deep deletions in brain versus lung primary samples. Immune infiltration measures were similar between lung and brain metastasis pairs (LUMP-score=0.64) consistent with high immune cell infiltration. CONCLUSION: In this EGFR-mutant lung adenocarcinomas and matched brain metastases, differentially methylated CpG sites and CNV alterations are identified that distinguish lung from brain samples. Further work with additional matched samples may further elucidate signatures specific to brain metastasis and aid in our understanding of the mechanisms of brain metastasis. Oxford University Press 2019-08-12 /pmc/articles/PMC7213095/ http://dx.doi.org/10.1093/noajnl/vdz014.022 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Mamatjan, Yasin
Zuccato, Jeffrey
Karimi, Shirin
Cabanero, Michael
Weiss, Jessica
Sorotsky, Hadas
Tsao, Ming
Shepherd, Frances
Aldape, Kenneth
Zadeh, Gelareh
BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
title BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
title_full BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
title_fullStr BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
title_full_unstemmed BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
title_short BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
title_sort bsci-26. comparative methylation profiling of egfr mutant lung adenocarcinoma and paired brain metastasis
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213095/
http://dx.doi.org/10.1093/noajnl/vdz014.022
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