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Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma
- Source :
- Genome Medicine, Vol 11, Iss 1, Pp 1-3 (2019), Genome Medicine
- Publication Year :
- 2019
- Publisher :
- BMC, 2019.
-
Abstract
- 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.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.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.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.
- Subjects :
- Mesothelioma
0301 basic medicine
Oncology
medicine.medical_specialty
lcsh:QH426-470
medicine.medical_treatment
Immune checkpoint inhibitors
lcsh:Medicine
Haploinsufficiency
03 medical and health sciences
0302 clinical medicine
Internal medicine
Biomarkers, Tumor
Tumor Microenvironment
Genetics
medicine
Humans
Molecular Biology
Peritoneal Neoplasms
Genetics (clinical)
Predictive biomarker
BAP1
Tumor microenvironment
business.industry
Tumor Suppressor Proteins
lcsh:R
Immunotherapy
medicine.disease
Research Highlight
respiratory tract diseases
lcsh:Genetics
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
Peritoneal mesothelioma
Molecular Medicine
business
Ubiquitin Thiolesterase
Subjects
Details
- Language :
- English
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Genome Medicine
- Accession number :
- edsair.doi.dedup.....3bd8c1e3eccaf823a9ad63702435def5