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BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma
BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhib...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378747/ https://www.ncbi.nlm.nih.gov/pubmed/30777124 http://dx.doi.org/10.1186/s13073-019-0620-3 |
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author | Shrestha, Raunak Nabavi, Noushin Lin, Yen-Yi Mo, Fan Anderson, Shawn Volik, Stanislav Adomat, Hans H. Lin, Dong Xue, Hui Dong, Xin Shukin, Robert Bell, Robert H. McConeghy, Brian Haegert, Anne Brahmbhatt, Sonal Li, Estelle Oo, Htoo Zarni Hurtado-Coll, Antonio Fazli, Ladan Zhou, Joshua McConnell, Yarrow McCart, Andrea Lowy, Andrew Morin, Gregg B. Chen, Tianhui Daugaard, Mads Sahinalp, S. Cenk Hach, Faraz Le Bihan, Stephane Gleave, Martin E. Wang, Yuzhuo Churg, Andrew Collins, Colin C. |
author_facet | Shrestha, Raunak Nabavi, Noushin Lin, Yen-Yi Mo, Fan Anderson, Shawn Volik, Stanislav Adomat, Hans H. Lin, Dong Xue, Hui Dong, Xin Shukin, Robert Bell, Robert H. McConeghy, Brian Haegert, Anne Brahmbhatt, Sonal Li, Estelle Oo, Htoo Zarni Hurtado-Coll, Antonio Fazli, Ladan Zhou, Joshua McConnell, Yarrow McCart, Andrea Lowy, Andrew Morin, Gregg B. Chen, Tianhui Daugaard, Mads Sahinalp, S. Cenk Hach, Faraz Le Bihan, Stephane Gleave, Martin E. Wang, Yuzhuo Churg, Andrew Collins, Colin C. |
author_sort | Shrestha, Raunak |
collection | PubMed |
description | BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT’nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-019-0620-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6378747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63787472019-02-28 BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma Shrestha, Raunak Nabavi, Noushin Lin, Yen-Yi Mo, Fan Anderson, Shawn Volik, Stanislav Adomat, Hans H. Lin, Dong Xue, Hui Dong, Xin Shukin, Robert Bell, Robert H. McConeghy, Brian Haegert, Anne Brahmbhatt, Sonal Li, Estelle Oo, Htoo Zarni Hurtado-Coll, Antonio Fazli, Ladan Zhou, Joshua McConnell, Yarrow McCart, Andrea Lowy, Andrew Morin, Gregg B. Chen, Tianhui Daugaard, Mads Sahinalp, S. Cenk Hach, Faraz Le Bihan, Stephane Gleave, Martin E. Wang, Yuzhuo Churg, Andrew Collins, Colin C. Genome Med Research BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT’nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-019-0620-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-18 /pmc/articles/PMC6378747/ /pubmed/30777124 http://dx.doi.org/10.1186/s13073-019-0620-3 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Shrestha, Raunak Nabavi, Noushin Lin, Yen-Yi Mo, Fan Anderson, Shawn Volik, Stanislav Adomat, Hans H. Lin, Dong Xue, Hui Dong, Xin Shukin, Robert Bell, Robert H. McConeghy, Brian Haegert, Anne Brahmbhatt, Sonal Li, Estelle Oo, Htoo Zarni Hurtado-Coll, Antonio Fazli, Ladan Zhou, Joshua McConnell, Yarrow McCart, Andrea Lowy, Andrew Morin, Gregg B. Chen, Tianhui Daugaard, Mads Sahinalp, S. Cenk Hach, Faraz Le Bihan, Stephane Gleave, Martin E. Wang, Yuzhuo Churg, Andrew Collins, Colin C. BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
title | BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
title_full | BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
title_fullStr | BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
title_full_unstemmed | BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
title_short | BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
title_sort | bap1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378747/ https://www.ncbi.nlm.nih.gov/pubmed/30777124 http://dx.doi.org/10.1186/s13073-019-0620-3 |
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