BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

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

†Contributed equally

Genome Medicine201911:8

https://doi.org/10.1186/s13073-019-0620-3

Received: 20 August 2018
Accepted: 7 February 2019
Published: 18 February 2019

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.