Molecular alterations and potential actionable mutations in peritoneal mesothelioma: a scoping review of high-throughput sequencing studies

Our plain-English summary of Molecular alterations and potential actionable mutations in peritoneal mesothelioma: a scoping review of high-throughput sequencing studies, by M.V. Dietz, J.P. van Kooten, M.S. Paats, et al (ESMO Open, 2023).

The study

• Authors: M.V. Dietz, J.P. van Kooten, M.S. Paats, J.G.V.J. Aerts, C. Verhoef, E.V.E. Madsen, H.J. Dubbink, J.H. von der Thüsen
• Journal: ESMO Open
• Published: 2023;8(4):101600
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Peritoneal mesothelioma (PeM) is a rare malignancy with a poor prognosis. Currently there is a lack of effective systemic therapies. Due to the rarity of PeM, it is challenging to study new treatment options. Off-label use of targeted drugs could be an effective approach. This scoping review aims to explore the genomic landscape of PeM to identify potential therapeutic targets.

Materials And Methods: A systematic literature search of Embase, Medline, Web of Science, the Cochrane Library, and Google Scholar was carried out up to 1 November 2022. Studies that reported on molecular alterations in PeM detected by high-throughput sequencing techniques were included. Genes that were altered in ≥1% of PeMs were selected for the identification of potential targeted therapies.

Results: Thirteen articles were included, comprising 824 PeM patients. In total, 142 genes were altered in ≥1% of patients, of which 7 genes were altered in ≥10%. BAP1 was the most commonly altered gene (50%). Other commonly altered genes were NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%), and SETD2 (13%). In total, 17% of PeM patients were carriers of a germline mutation, mainly in BAP1 (7%).

Conclusions: This scoping review provides an overview of the mutational landscape of PeM. Germline mutations might be a larger contributor to the incidence of PeM than previously thought. Currently available targeted therapy options are limited, but several targeted agents [such as poly (ADP-ribose) polymerase (PARP), enhancer of zeste homolog 2 (EZH2), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors] were identified that might provide new targeted therapy options in the future.

Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

In plain English

This was a scoping review, not a new study of patients. The authors searched literature databases up to October 2022 for studies that used high-throughput genetic sequencing to find gene changes in peritoneal mesothelioma (mesothelioma of the abdominal lining). They included 13 articles covering 824 patients. The review did not analyse the included patients' asbestos exposure, though the authors discussed it. Among genes tested in at least 10% of patients, 52 were altered in at least 1% of patients. The most commonly altered were BAP1 (49%), NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%) and SETD2 (12%). Of 96 patients tested for inherited (germline) mutations, 16 (17%) carried one, including 7 (7%) with an inherited BAP1 mutation. No targeted drugs were approved for peritoneal mesothelioma. For 12 of the 52 genes, approved drugs existed for other cancers. The authors concluded that genetic predisposition appeared to play a larger role in peritoneal than in pleural mesothelioma, and that current targeted options were very limited. They noted that the included studies differed in their patients and sequencing methods.

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: Scoping review of published high-throughput sequencing studies (no meta-analysis)
• Who was studied: 13 published articles comprising 824 patients with peritoneal mesothelioma. Of the 746 with known sex, 347 (47%) were male. Of the 268 with reported histology, 233 (87%) were epithelioid.
• Exposure: The review compiled likely pathogenic gene alterations found by high-throughput sequencing in peritoneal mesothelioma tumors, plus germline (inherited) mutations. It did not analyse the included patients' asbestos or fiber exposure. The authors discussed asbestos exposure only in the discussion. There they suggested that genetic predisposition might explain why the association with asbestos exposure is less evident for peritoneal than for pleural mesothelioma.
• Main results:
  • Among genes tested in at least 10% of patients, 52 were altered in at least 1%. The most commonly altered genes in peritoneal mesothelioma were BAP1 (49%), NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%) and SETD2 (12%).
  • Of 96 patients with peritoneal mesothelioma who underwent germline testing, 16 (17%) carried a germline mutation, mainly in BAP1 (7%).
  • In one included study (Panou et al.), 11 of 44 patients with peritoneal mesothelioma (25%) carried a germline mutation.
  • Seven articles reported on both forms. Compared with pleural mesothelioma in those articles, CDKN2A/B alterations were less common in peritoneal mesothelioma and PBRM1 alterations were more common.
  • No targeted therapies were available for peritoneal mesothelioma. For 12 of the 52 genes, approved targeted therapies existed for other cancers.
  • Tumor mutational burden was low in most peritoneal mesothelioma tumors.
• The authors' conclusion: The authors concluded that BAP1 alterations were most common and that up to 17% of patients carried a germline mutation. They also concluded that genetic predisposition plays a larger role in peritoneal than in pleural mesothelioma. They found currently available targeted therapy options very limited, although some trials and drugs approved for other cancers might offer future options.
• Limitations the authors state:
  • The included studies were heterogeneous and lacked relevant data.
  • The studies used different DNA sequencing methods.
  • Data-processing pipelines differed between studies, so their sensitivity to detect alterations varied.
  • Not all studies provided full mutational data.
  • Meta-analysis was not feasible, and risk of bias was not assessed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Prognosis, BAP1, CDKN2A, Germline Mutation, Targeted Therapy.

Related studies

• Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing — N. Oumi, H. Itamochi, et al. (2016)
• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)
• Identification of actionable mutations in malignant pleural mesothelioma — T. Shukuya, M. Serizawa, et al. (2014)
• Genomic sequencing of multicystic mesothelioma finds cohesin complex mutations associated with disease recurrence in patients referred for cytoreductive surgery and HIPEC — J. Gibson, N.J. Carr, et al. (2026)
• Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing — B.S. Sheffield, A.V. Tinker, et al. (2015)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)

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