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BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

ABSTRACT: 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.

SUBMITTER: Shrestha R

PROVIDER: S-EPMC6378747 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

Shrestha Raunak R Nabavi Noushin N Lin Yen-Yi YY Mo Fan F Anderson Shawn S Volik Stanislav S Adomat Hans H HH Lin Dong D Xue Hui H Dong Xin X Shukin Robert R Bell Robert H RH McConeghy Brian B Haegert Anne A Brahmbhatt Sonal S Li Estelle E Oo Htoo Zarni HZ Hurtado-Coll Antonio A Fazli Ladan L Zhou Joshua J McConnell Yarrow Y McCart Andrea A Lowy Andrew A Morin Gregg B GB Chen Tianhui T Daugaard Mads M Sahinalp S Cenk SC Hach Faraz F Le Bihan Stephane S Gleave Martin E ME Wang Yuzhuo Y Churg Andrew A Collins Colin C CC

Genome medicine 20190218 1

<h4>Background</h4>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.<h4>Methods</h4>To search for novel therapeutic targets for PeM, we performed a comprehensive integrat ...[more]

PMID: 30777124

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Project description:Malignant mesothelioma is a rare cancer that arises from the mesothelial cells that line the pleural cavity and less commonly from the peritoneal lining of the abdomen and pelvis. Most pleural mesotheliomas arise in patients with a history of asbestos exposure, whereas the association of peritoneal mesotheliomas with exposure to asbestos and other potential carcinogens is less clear, suggesting that the genetic alterations that drive malignant peritoneal mesothelioma may be unique from those in pleural mesothelioma. Treatment options for all malignant mesotheliomas are currently limited, with no known targeted therapies available. To better understand the molecular pathogenesis of malignant peritoneal mesothelioma, we sequenced 510 cancer-related genes in 13 patients with malignant mesothelioma arising in the peritoneal cavity. The most frequent genetic alteration was biallelic inactivation of the BAP1 gene, which occurred in 9/13 cases, with an additional two cases demonstrating monoallelic loss of BAP1. All 11 of these cases demonstrated loss of BAP1 nuclear staining by immunohistochemistry, whereas two tumors without BAP1 alteration and all 42 cases of histologic mimics in peritoneum (8 multilocular peritoneal inclusion cyst, 6 well-differentiated papillary mesothelioma of the peritoneum, 16 adenomatoid tumor, and 12 low-grade serous carcinoma of the ovary) demonstrated intact BAP1 nuclear staining. Additional recurrently mutated genes in this cohort of malignant peritoneal mesotheliomas included NF2 (3/13), SETD2 (2/13), and DDX3X (2/13). While these genes are known to be recurrently mutated in pleural mesotheliomas, the frequencies are distinct in peritoneal mesotheliomas, with nearly 85% of peritoneal tumors harboring BAP1 alterations versus only 20-30% of pleural tumors. Together, these findings demonstrate the importance of epigenetic modifiers including BAP1, SETD2, and DDX3X in mesothelial tumorigenesis and suggest opportunities for targeted therapies.

Dataset Information

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

Publications

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

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