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Updated: Aug 20, 2025
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications
Hatice Ulku Osmanbeyoglu1,2,3, Drake Palmer2, April Sagan1,2
1Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15206, USA.
Abstract:
Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.
Insights
Genomic alterations in tumor suppressor genes (TSGs) impact malignant pleural mesothelioma (MPM) outcomes. BAP1 alterations alone correlate with better survival and potential immunotherapy response in MPM.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options.
- Frequent genomic alterations in tumor suppressor genes (TSGs) like BAP1, CDKN2A/B, and NF2 are observed in MPM.
- The differential impact of single versus multiple TSG alterations on MPM remains unclear.
Purpose of the Study:
- To investigate the distinct effects of TSG alterations on MPM biology and patient outcomes.
- To explore the relationship between TSG genotypes and the tumor immune microenvironment.
- To identify potential biomarkers for immunotherapy response in MPM.
Main Methods:
- Analysis of somatic mutations and copy number losses in key TSGs (BAP1, CDKN2A/B, NF2) in MPM.
- Correlation of TSG alterations with patient survival, immune cell infiltration, and gene expression profiles.
- Assessment of associations with immune checkpoint blockade therapy response signatures.
Main Results:
- MPM tumors with BAP1 alterations alone showed longer overall survival compared to those with CDKN2A/B and/or NF2 alterations.
- BAP1-altered tumors exhibited a distinct immunogenic subtype with unique transcriptional patterns.
- CDKN2A/B alterations were consistently linked to poorer clinical outcomes.
- BAP1 alterations correlated with PD-1 therapy response signatures and elevated LAG3/VISTA expression.
Conclusions:
- TSG genotypes significantly influence MPM biology, immune microenvironment, and clinical trajectory.
- BAP1 alterations may serve as a predictive biomarker for immune checkpoint blockade therapy in MPM.
- Understanding TSG alterations provides a basis for developing personalized MPM treatment strategies.
