Journal Article

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

McCart, Andrea, Lowy, Andrew, McConeghy, Brian, Hurtado-Coll, Antonio, Shrestha, Raunak, Haegert, Anne, Morin, Gregg B., Collins, Colin C., Lin, Yen-Yi, Le Bihan, Stephane, Adomat, Hans H., Daugaard, Mads, Nabavi, Noushin, Fazli, Ladan, McConnell, Yarrow, Mo, Fan, Dong, Xin, Churg, Andrew, Lin, Dong, Oo, Htoo Zarni, Li, Estelle, Bell, Robert H., Zhou, Joshua, Shukin, Robert, Brahmbhatt, Sonal, Chen, Tianhui, Hach, Faraz, Xue, Hui, Volik, Stanislav, Sahinalp, S. Cenk, Anderson, Shawn, Gleave, Martin E., Wang, Yuzhuo

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Algorithms / Analysis / BAP1 / Bioinformatics / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / Cancer treatment / Care and treatment / Chemotherapy / Chromatin / Chromatin remodeling / Clinical trials / Copy number / Cyclin-dependent kinases / Debulking / Deoxyribonucleic acid / DNA / DNA repair / EDTA / From genome integrity to cancer: mechanisms and translational opportunities / Gastric cancer / Gene expression / Genes / Genetic aspects / Genomes / Genomics / Haploinsufficiency / Human Genetics / Humans / Immune checkpoint inhibitors / Immunogenicity / Immunotherapy / Inflammation / Medicine/Public Health / Mesothelioma / Mesothelioma - classification / Mesothelioma - genetics / Mesothelioma - therapy / Metabolomics / Mutation / Oncology / Patients / Peritoneal mesothelioma / Peritoneal Neoplasms - classification / Peritoneal Neoplasms - genetics / Peritoneal Neoplasms - therapy / Peritoneum / Precision medicine / Precision oncology / Proteins / Proteomes / Receptor mechanisms / Surgery / Systems Biology / Therapeutic applications / Tumor immunosurveillance / Tumor Microenvironment / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumors / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism