BAP1 Mutations and Pleural Mesothelioma: Genetic Insights, Clinical Implications, and Therapeutic Perspectives

Our plain-English summary of BAP1 Mutations and Pleural Mesothelioma: Genetic Insights, Clinical Implications, and Therapeutic Perspectives, by S. Cedres, A. Valdivia, I. Priano, et al (Cancers, 2025).

The study

• Authors: S. Cedres, A. Valdivia, I. Priano, P. Rocha, P. Iranzo, N. Pardo, A. Martinez-Marti, E. Felip
• Journal: Cancers
• Published: 2025;17(9)
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is a locally aggressive tumor associated with asbestos exposure. Despite legislative efforts to regulate asbestos use, its incidence continues to rise in some parts of the world. Chemotherapy and immunotherapy have improved survival in PM patients, but overall survival remains poor. Molecular analysis of PM patients has shown that most alterations occur in tumor suppressor genes, with BAP1 being the most frequently affected. Patients with germline BAP1 mutations have been reported to have a better prognosis, but this is not observed in those with somatic mutations. Interest in developing drugs targeting patients with BAP1 loss has led to several phase II studies in recent years. Unfortunately, initial results have not been very promising. In this review, we conclude that, at this time, with the contradictory results from studies and the limited number of patients evaluated, BAP1, the most commonly altered gene in PM, is not yet suitable for use in clinical practice as a prognostic or predictive factor. Future studies are needed to establish the prognostic or predictive value of BAP1.

In plain English

This article was a review of published research on BAP1, the gene most often altered in pleural mesothelioma (PM). It reported no new patient data, did not describe how studies were chosen, and discussed asbestos exposure only as background, analyzing no exposure data. Studies it reviewed reported BAP1 loss in up to 60% of PM, with most BAP1 mutations acquired in the tumor (somatic). Inherited (germline) BAP1 mutations were reported in 9–12% of PM patients, and median survival for those patients was around 5–7 years. On whether BAP1 status predicts survival, the reviewed studies disagreed. A meta-analysis of 698 patients found no statistically significant survival difference by BAP1 status. One retrospective study reported longer survival with BAP1 loss after first-line platinum and pemetrexed chemotherapy (20.1 versus 7.3 months). Trials of drugs aimed at BAP1-deficient tumors showed modest activity. The authors concluded that BAP1 is not yet a reliable predictor of treatment response. They noted that all evidence on BAP1 and prognosis came from retrospective studies, mostly with limited numbers of patients, and that the two chemotherapy studies were also retrospective. Some numbers differ between the article's text and its tables.

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: narrative review of published clinical and preclinical studies (no new patient data; search and selection methods not described)
• Who was studied: Published studies of BAP1 in mesothelioma: patient series, clinical trials, meta-analyses, and cell-line and mouse studies, reviewed by authors at the Vall d'Hebron Institute of Oncology, Barcelona, Spain
• Exposure: BAP1 gene alterations in pleural mesothelioma, both somatic (in the tumor) and germline (inherited). Asbestos is discussed as background: as a risk factor for PM, in incidence trends tied to regulation, and as a cause of DNA damage. No fiber types were named and no exposure data were analyzed.
• Main results:
  • In the studies reviewed, BAP1 loss was seen in up to 60% of PM, and most BAP1 mutations in PM were somatic (70–80%).
  • Germline BAP1 mutations were reported in 9–12% of PM patients.
  • For patients with germline BAP1 alterations, median survival was reported as around 5–7 years, with 26% surviving 10 or more years.
  • Studies of BAP1 loss and survival gave conflicting results. A meta-analysis of 698 patients found no statistically significant survival difference by BAP1 status; the article's table lists it as a non-significant increase in survival with BAP1 loss.
  • In one large retrospective series of patients given first-line platinum and pemetrexed, those whose tumors had BAP1 loss had longer median survival (20.1 versus 7.3 months).
  • In a phase II trial of the EZH2 inhibitor tazemetostat in 74 relapsed patients, the overall response rate was 3% and the 12-week disease control rate was 51%.
  • In the MiST1 trial (26 patients), the PARP inhibitor rucaparib showed only modest activity, and BAP1 or BRCA1 loss did not predict response.
  • The authors stated that the available studies, which involved limited numbers of patients, did not allow a conclusion that BAP1 predicts response to immunotherapy.
• The authors' conclusion: The authors concluded that BAP1 is a frequent alteration in PM but is not currently a reliable predictor of treatment response, and that BAP1 analysis is for now reserved for research purposes.
• Limitations the authors state:
  • All data on the prognostic value of BAP1 came from retrospective studies, most with a limited number of patients.
  • The two studies suggesting BAP1 predicts survival after platinum chemotherapy were retrospective and need prospective validation.
  • Findings on second-line chemotherapy came from a limited number of patients.
  • Detecting BAP1 mutations is technically difficult, and mutation types vary.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Pleural Mesothelioma, Asbestos Exposure, Chemotherapy, Immunotherapy, Overall Survival, Tumor Suppressor Gene, BAP1 Tumor Predisposition Syndrome.

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