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Updated: Dec 19, 2025
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Molecular characterization of diffuse malignant peritoneal mesothelioma
Yin P Hung1,2, Fei Dong3, Matthew Torre3
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. yphung@mgh.harvard.edu.
Abstract:
Malignant peritoneal mesothelioma is a rare aggressive tumor that arises from the peritoneal lining. While recurrent BAP1 mutations have been identified in a subset of mesotheliomas, molecular characteristics of peritoneal mesotheliomas, including those lacking BAP1 alterations, remain poorly understood. Using targeted next-generation sequencing, we examined the molecular features of 26 diffuse malignant peritoneal mesotheliomas. As part of an exploratory analysis, we analyzed an additional localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci. Genomic characterization identified categories of diffuse malignant peritoneal mesotheliomas: The first group included 18 (69%) tumors with recurrent BAP1 alterations, with eight (31%) having more than one BAP1 alterations, and concomitant alterations in PBRM1 (46%) and SETD2 (35%). All tumors with complete loss of BAP1 expression by immunohistochemistry harbored BAP1 molecular alterations. PBRM1 alterations were significantly enriched in the BAP1-altered cohort. Frequent copy number loss of BAP1, ARID1B, PRDM1, PBRM1, SETD2, NF2, and CDKN2A was noted. The second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published. One TP53-mutant biphasic mesothelioma showed evidence of genomic near-haploidization showing loss of heterozygosity of all chromosomes except 5, 7, 16, and 20. The localized peritoneal mesothelioma harbored a nonsense CHEK2 mutation, and the well-differentiated papillary mesothelioma with invasive foci harbored no reportable variants. In conclusion, we described the genetic categories of diffuse malignant peritoneal mesotheliomas, with BAP1-mutant and BAP1-wild-type groups. Our findings implicated DNA repair, epigenetics, and cell cycle regulation in the pathogenesis of peritoneal mesotheliomas, with identification of potential therapeutic targets.
Insights
This study categorizes malignant peritoneal mesothelioma into BAP1-mutant and BAP1-wild-type groups. Findings reveal key genetic alterations, implicating DNA repair and epigenetics in mesothelioma development and suggesting therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Malignant peritoneal mesothelioma is a rare, aggressive cancer.
- Molecular drivers, especially in BAP1-wild-type cases, are poorly understood.
Purpose of the Study:
- To molecularly characterize diffuse malignant peritoneal mesotheliomas.
- To identify distinct genetic subtypes and potential therapeutic targets.
Main Methods:
- Targeted next-generation sequencing of 26 diffuse malignant peritoneal mesotheliomas.
- Exploratory analysis of additional peritoneal mesothelioma subtypes.
- Immunohistochemistry for BAP1 expression.
Main Results:
- Two main groups identified: BAP1-altered (69%) and BAP1-wild-type (31%).
- BAP1-altered tumors frequently had PBRM1 and SETD2 alterations; BAP1 loss correlated with expression loss.
- BAP1-wild-type tumors showed diverse mutations including TP53, TRAF7, SUZ12, and ALK rearrangements.
Conclusions:
- Diffuse malignant peritoneal mesothelioma can be genetically classified into BAP1-mutant and BAP1-wild-type categories.
- Pathogenesis involves DNA repair, epigenetics, and cell cycle regulation.
- Identified genetic alterations may serve as therapeutic targets.
