Molecular characterization of diffuse malignant peritoneal mesothelioma

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.

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Fig. 1: Landscape of clinicopathologic and molecular features of peritoneal mesotheliomas in this study.
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Acknowledgements

We thank Ms. Mei Zheng and the immunohistochemistry laboratory; Ms. Michele Baltay at the Center for Advanced Molecular Diagnostics, Brigham and Women’s Hospital, for technical support.

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Correspondence to Yin P. Hung or Lucian R. Chirieac.

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There is no disclosure from YPH, FD, MT, and CPC. RB has served on the Advisory boards for Myriad, Exosome Diagnostics, and CollaboRx and received support from the National Cancer Institute and investigator-initiated industry grants from Castle Biosciences, Exosome Diagnostics, Genentech-Roche, Gritstone, HTG, Merck, Myriad, Novartis, PamGene, Siemens, Verastem, MedGenome, and Epizyme. LRC undertakes medicolegal work related to mesothelioma. All financial disclosures listed above do not apply to the current study, which is not associated with a specific source of funding.

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Hung, Y.P., Dong, F., Torre, M. et al. Molecular characterization of diffuse malignant peritoneal mesothelioma. Mod Pathol 33, 2269–2279 (2020). https://doi.org/10.1038/s41379-020-0588-y

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