BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

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

doi:10.1186/s13073-019-0620-3

Abstract

BackgroundMalignant 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.MethodsTo 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.ResultsWe 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.ConclusionsOur 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.

Highlights

Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen
Landscape of somatic mutations in PeM To investigate the landscape of somatic gene mutations in PeM, we performed high-coverage whole exome sequencing of 19 tumors and 16 matched normal samples (Additional file 2: Table S1)
We discovered that the immune marker gene score was strongly correlated with the stromal marker gene score (Fig. 4a) suggesting possible leukocyte infiltration in PeM from the tumor microenvironment

Summary

Introduction

Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. Malignant mesothelioma is a rare but aggressive cancer that arises from the internal membrane lining of the pleura and the peritoneum. Epidemiological studies suggest that unlike PM, asbestos exposure plays a far smaller role in the etiology of PeM tumors [2]. Previous studies in mesotheliomas have revealed that over 60% of mesotheliomas harbor BRCA1 associated protein 1 (BAP1) inactivating mutation or copy number loss, making BAP1 the most commonly altered gene in this malignancy [3,4,5,6,7]. Genome information coupled with transcriptome and proteome information is more likely to be successful in revealing potential therapeutic modalities

Methods

Results

Discussion

Conclusion