A new comprehensive review published in Oncogene maps the molecular mechanisms of BAP1 tumor suppressor loss in mesothelioma and identifies potential clinical opportunities for targeted treatment. The paper synthesizes current understanding of how BAP1 inactivation drives mesothelioma development and what therapeutic approaches might exploit this vulnerability.
BAP1: The Most Common Mesothelioma Mutation
BAP1 (BRCA1-associated protein-1) is a tumor suppressor gene that functions as a deubiquitinase—an enzyme that removes ubiquitin tags from proteins, affecting their stability and function. BAP1 inactivation is the most common molecular alteration in mesothelioma.
Prevalence
| Population | BAP1 Alteration Rate |
|---|---|
| All mesotheliomas | About 65% |
| Mesothelioma in situ | Highest (early event) |
| Germline carriers | 35% develop mesothelioma |
BAP1 mutations appear to be an early event in mesothelioma development, often present even in mesothelioma in situ—the earliest identifiable stage of the disease.
How BAP1 Loss Drives Cancer
The review details multiple mechanisms by which BAP1 inactivation promotes mesothelioma:
Epigenetic Dysregulation
BAP1 normally interacts with Polycomb-group complexes that regulate which genes are turned on or off. When BAP1 is lost:
- Polycomb repressive complex 2 (PRC2) becomes hyperactive
- Abnormal histone methylation silences tumor suppressor genes
- Cells lose normal growth controls
DNA Repair Defects
BAP1 plays a role in repairing DNA double-strand breaks. Loss of BAP1:
- Impairs homologous recombination repair
- Increases genomic instability
- Makes cells more susceptible to DNA-damaging agents
Metabolic Changes
The review notes that BAP1 loss alters cellular metabolism in ways that may promote cancer cell survival and growth.
Asbestos fibers cause DNA damage and chronic inflammation. In cells with defective BAP1, this damage cannot be properly repaired, dramatically increasing cancer risk. This explains why BAP1 mutation carriers are exceptionally vulnerable to asbestos-related cancers.
Clinical Implications
Better Prognosis (Sometimes)
Research suggests that patients with germline BAP1 mutations—those born with the mutation—may have better outcomes than typical mesothelioma patients:
| Patient Group | Prognosis |
|---|---|
| Germline BAP1 mutation | Better survival |
| Somatic BAP1 mutation only | No survival benefit |
| BAP1 wild-type | Standard prognosis |
Platinum Sensitivity
Data suggest BAP1-mutant tumors may be more sensitive to platinum-based chemotherapy (cisplatin, carboplatin). This could help identify patients most likely to benefit from standard first-line treatment.
Therapeutic Opportunities
EZH2 Inhibitors
The most promising targeted approach involves EZH2 inhibitors. EZH2 is a component of the PRC2 complex that becomes dysregulated when BAP1 is lost.
Several EZH2 inhibitors are in development:
- Tazemetostat (FDA-approved for other cancers)
- Other compounds in clinical trials
Initial phase II trials of drugs targeting BAP1-deficient tumors have shown limited success. The review notes that “initial results have not been very promising,” but research continues to refine patient selection and drug combinations.
Other Potential Targets
The review identifies additional therapeutic opportunities:
| Target | Rationale |
|---|---|
| PARP inhibitors | Exploit DNA repair defects |
| HDAC inhibitors | Address epigenetic changes |
| Metabolic inhibitors | Target altered cell metabolism |
Genetic Testing Considerations
Who Should Consider Testing
BAP1 germline testing may be appropriate for:
- Mesothelioma patients diagnosed at younger ages
- Patients with family history of mesothelioma
- Patients with multiple primary cancers
- Those with uveal melanoma or kidney cancer (also linked to BAP1)
The BAP1 Cancer Syndrome
Carriers of germline BAP1 mutations face elevated risk for multiple cancers:
- Mesothelioma (35% lifetime risk)
- Uveal melanoma
- Cutaneous melanoma
- Renal cell carcinoma
- Other malignancies
Among 238 BAP1 mutation carriers studied, 45.2% developed multiple cancers.
Implications for Research
The review highlights several priorities for future investigation:
- Better biomarkers to identify BAP1-deficient tumors likely to respond to targeted therapy
- Combination strategies pairing EZH2 inhibitors with immunotherapy or chemotherapy
- Early detection methods for BAP1 mutation carriers
- Prevention strategies including strict asbestos avoidance for carriers
Related Reading
- Michele Carbone: BAP1 and Mesothelioma Discovery
- Mesothelioma Causes: Genetic Factors
- Mesothelioma Clinical Trials
What is BAP1?▼
BAP1 (BRCA1-associated protein-1) is a tumor suppressor gene that encodes an enzyme involved in DNA repair, gene regulation, and cell metabolism. It is the most commonly mutated gene in mesothelioma, with approximately 65% of cases showing BAP1 inactivation.
Does BAP1 mutation status affect prognosis?▼
Patients with inherited (germline) BAP1 mutations tend to have better survival than typical mesothelioma patients. However, this survival benefit is not seen in patients whose tumors acquired BAP1 mutations later (somatic mutations).
Are there targeted treatments for BAP1-deficient mesothelioma?▼
EZH2 inhibitors are the most promising targeted approach, as they address the epigenetic dysregulation caused by BAP1 loss. However, clinical trial results have been mixed so far, and research continues to identify optimal treatment strategies.
Should mesothelioma patients get BAP1 genetic testing?▼
BAP1 testing may be valuable for younger patients, those with family history of mesothelioma or related cancers, and those with multiple primary cancers. Results can inform family screening and may eventually guide treatment selection.