BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

Our plain-English summary of BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma, by R. Shrestha, N. Nabavi, Y.Y. Lin, et al (Genome Medicine, 2019).

The study

• Authors: R. Shrestha, N. Nabavi, Y.Y. Lin, F. Mo, S. Anderson, S. Volik, H.H. Adomat, D. Lin, H. Xue, X. Dong, R. Shukin, R.H. Bell, B. McConeghy, A. Haegert, S. Brahmbhatt, E. Li, H.Z. Oo, A. Hurtado-Coll, L. Fazli, J. Zhou, Y. McConnell, A. McCart, A. Lowy, G.B. Morin, T. Chen, M. Daugaard, S.C. Sahinalp, F. Hach, S. Le Bihan, M.E. Gleave, Y. Wang, A. Churg, C.C. Collins
• Journal: Genome Medicine
• Published: 2019;11(1):8
• Cited by: 117 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study analysed malignant peritoneal mesothelioma (PeM), a cancer of the abdominal lining. The authors examined 19 untreated tumors from 18 surgical patients in Vancouver, Toronto and San Diego. Two pathologists classed all tumors as epithelioid. All 19 tumors had their DNA sequenced; gene activity (RNA) was measured in 15 and proteins in 16. Asbestos exposure was listed as unknown for 6 tumors, no for 12 and yes for 1, and the study did not analyse asbestos. BAP1 was the most frequently mutated gene (5 of 19 tumors). A chromosome region containing BAP1 (3p21) was lost in 8 of 19 tumors, which the authors called BAP1del. These tumors showed lower BAP1 gene activity, signs of T-cell infiltration, and higher activity of several immune checkpoint genes, including PD1, PD-L1, CTLA4, LAG3 and ICOS. In pleural mesothelioma data from the TCGA project, the authors saw no significant difference in checkpoint gene expression between tumors with and without 3p21 loss. The authors concluded that BAP1del tumors form a distinct subtype and are candidates for immune checkpoint blockade therapies. The study did not test any treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory molecular study (integrated analysis of tumor DNA, RNA and protein) of surgical tumor samples; no treatment was tested
• Who was studied: 19 fresh-frozen, treatment-naive malignant peritoneal mesothelioma tumors from 18 patients undergoing cytoreductive surgery at Vancouver General Hospital, Mount Sinai Hospital (Toronto) and Moores Cancer Centre (San Diego); one patient contributed 2 tumors. Both pathologists classed all 19 tumors as epithelioid PeM. Whole exome sequencing covered 19 tumors, RNA sequencing 15 tumors, and mass spectrometry 16 tumors. Dates are not given.
• Exposure: The study did not examine asbestos as an exposure. The patient table records asbestos exposure as Unknown for 6 tumors, No for 12 tumors and Yes for 1 tumor (MESO-19). The comparison studied was BAP1 status: tumors with loss of the 3p21 (BAP1) region (BAP1del) versus tumors with that region intact (BAP1intact).
• Main results:
  • Across the tumors, the authors identified 346 unique non-silent mutations affecting 202 genes. BAP1 was the most frequently mutated gene, mutated in 5 of 19 tumors.
  • Chromosome region 3p21, which contains BAP1, was deleted on one or both copies in 8 of 19 tumors. These were called BAP1del; the rest were called BAP1intact.
  • BAP1 gene activity was lower in BAP1del tumors than in BAP1intact tumors (p value = 3 × 10^-4). Tumors that had lost both copies of BAP1 lacked BAP1 nuclear staining, while tumors that had lost one copy still showed it.
  • BAP1del tumors showed more infiltration of mast cells and T cells, and fewer plasma cells, NK cells and B cells, than BAP1intact tumors. BAP1del tumors stained positive for the T-cell markers CD3 and CD8.
  • Several immune checkpoint genes were more highly expressed in BAP1del tumors than in BAP1intact tumors: PDCD1 (PD1), CD274 (PD-L1), CD80, CTLA4, LAG3 and ICOS.
  • In pleural mesothelioma data from The Cancer Gene Atlas (TCGA) project, there was no significant difference in immune checkpoint gene expression between tumors with and without 3p21 loss.
  • Protein profiles of BAP1del and BAP1intact tumors did not form distinct groups, and BAP1 protein itself was not detected by mass spectrometry.
• The authors' conclusion: The authors concluded that BAP1 haploinsufficiency marks a distinct molecular subtype of PeM that is a candidate for immune checkpoint blockade therapies. They proposed BAP1 as a possible prognostic and predictive biomarker. They hypothesized that response rates in immunotherapy trials for PeM will improve if patients are grouped by BAP1 copy number status.
• Limitations the authors state:
  • BAP1 protein was not detected by mass spectrometry, which the authors attributed to likely technical limitations.
  • The gene activity patterns of BAP1intact and BAP1del tumors were distinct overall, but a few samples overlapped.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Peritoneal Mesothelioma, Cytoreductive Surgery, Chemotherapy, checkpoint inhibitors, Mesothelioma, Prognosis, Tumor Microenvironment.

Related studies

• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)
• Loss of BAP1 expression is very rare in peritoneal and gynecologic serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma — J. Andrici, J. Jung, et al. (2016)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma — C. Glass, L.M. Sholl, et al. (2020)
• BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas — N. Leblay, F. Leprêtre, et al. (2017)
• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)

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