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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.

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma