BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas

Our plain-English summary of BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas, by N. Leblay, F. Leprêtre, N. Le Stang, et al (Journal of Thoracic Oncology, 2017).

The study

• Authors: N. Leblay, F. Leprêtre, N. Le Stang, A. Gautier-Stein, L. Villeneuve, S. Isaac, D. Maillet, F. Galateau-Sallé, C. Villenet, S. Sebda, A. Goracci, G. Byrnes, J.D. McKay, M. Figeac, O. Glehen, F.N. Gilly, M. Foll, L. Fernandez-Cuesta, M. Brevet
• Journal: Journal of Thoracic Oncology
• Published: 2017;12(4):724-733
• Cited by: 68 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma.

Methods: Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples.

Results: We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex.

Conclusions: As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This study examined the tumor suppressor gene BAP1 in tumors from 46 patients with malignant peritoneal mesothelioma (26 men, 20 women) from the French MESOPATH and RENAPE networks. The authors sequenced 34 tumors for BAP1 mutations and tested 44 tumors for BAP1 protein in the cell nucleus. They combined these results with their earlier copy number (gene loss) data on 33 tumors. Mutations were found in 11 of 34 sequenced tumors (32%), copy number loss in 14 of 33 (42%), and loss of nuclear BAP1 protein in 25 of 44 (57%). Overall, 71% of the tumors analyzed carried at least one copy of BAP1 inactivated by copy number loss or mutation. Mutations were seen only in men. Professional asbestos exposure was reported for 8 of the 44 patients with this information (18%), all of them men. Loss of nuclear BAP1 protein (hazard ratio 0.27, 95% CI 0.09-0.79) and BAP1 mutation (hazard ratio 0.27, 95% CI 0.07-0.96) were each associated with better overall survival, independently of tumor histology, age and gender. The authors concluded that nuclear BAP1 protein is a good prognostic factor and a more reliable marker of complete loss of BAP1 activity than mutation or copy number loss.

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: Molecular pathology study of tumor samples (gene sequencing, protein staining, and earlier copy number data), with survival analysis
• Who was studied: 46 patients with malignant peritoneal mesothelioma (26 men, 20 women) from the French national networks MESOPATH and RENAPE, all treated with cytoreduction surgery and heated intraperitoneal chemotherapy. Most tumors were epithelioid (41), with 3 biphasic and 2 sarcomatoid. The survival analysis included only patients diagnosed between 1998 and 2012.
• Exposure: The study was about BAP1 gene alterations. Professional asbestos exposure was recorded by medical interview: 8 of the 44 patients with this information (18%), all of them men. Fiber types are not named.
• Main results:
  • BAP1 mutations (splicing, nonsense, missense and frame-shift) were found in 11 of the 34 tumors sequenced (32%).
  • In the authors' earlier work, BAP1 copy number loss had been found in 14 of the 33 tumors with copy number data (42%).
  • Loss of BAP1 nuclear protein expression was found in 25 of the 44 tumors stained (57%).
  • 71% of the peritoneal mesotheliomas analyzed carried at least one copy of BAP1 inactivated by copy number loss or mutation.
  • Loss of BAP1 nuclear expression was associated with better overall survival (HR 0.27, 95% CI 0.09-0.79, p=0.016), independently of tumor histology, age and gender.
  • Having a BAP1 mutation was associated with better overall survival (HR 0.27, 95% CI 0.07-0.96, p=0.04).
  • Having a BAP1 mutation and/or loss of nuclear expression was associated with survival (HR 0.24, 95% CI 0.08-0.69, p=0.007).
  • When copy number loss was added to this combination, the association with survival was not statistically significant (HR 0.47, 95% CI 0.12-1.71, p=0.25).
  • BAP1 mutations were observed only in men, a statistically significant difference by gender (p=0.003).
  • Professional asbestos exposure was observed only in men (p=0.007).
  • Loss of BAP1 expression was observed only in the epithelioid type.
• The authors' conclusion: The authors concluded that, as in pleural mesothelioma, BAP1 inactivation is frequent in peritoneal mesothelioma. They found that BAP1 nuclear protein expression is a good prognostic factor and a more reliable marker of complete loss of BAP1 activity than mutation or copy number loss.
• Limitations the authors state:
  • Germ-line (inherited) BAP1 status was unavailable for most samples, which limited the analysis of germ-line versus somatic mutations.
  • It is unclear whether the men-only occurrence of BAP1 mutations reflects biology or a sampling issue.
  • Non-epithelioid histological types were poorly represented in the series.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, Peritoneal Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Pleural Mesothelioma, Overall Survival, Histological Subtype.

Related studies

• Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array — P. Chirac, D. Maillet, et al. (2016)
• The value of BRCA-1-associated protein 1 expression and cyclin-dependent kinase inhibitor 2A deletion to distinguish peritoneal malignant mesothelioma from peritoneal location of carcinoma in effusion cytology specimens — W. Althakfi, S. Gazzo, et al. (2020)
• BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma — H. Alakus, S.E. Yost, et al. (2015)
• 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)
• Genetic Basis of Mesothelioma--More Than Asbestos Exposure — D. Lee (2016)
• Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions — I. Cozzi, F.A. Oprescu, et al. (2018)

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