Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths

Our plain-English summary of Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths, by A. Nash, J. Creaney (Current Oncology Reports, 2023).

The study

• Authors: A. Nash, J. Creaney
• Journal: Current Oncology Reports
• Published: 2023;25(12):1515-1522
• Type of article: Review
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose Of Review: In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to clinical practice.

Recent Findings: Advancements in sequencing technology have allowed the identification of driver mutations and improved our understanding of how these mutations may shape the mesothelioma tumour microenvironment. However, the identification of frequently mutated regions including CDKN2A, BAP1 and NF2 have, to date, not yet yielded targeted therapy options that outperform standard chemo- and immunotherapies. Similarly, the association between mutational profile and the immune microenvironment or immunotherapy response is not well characterised. Further research into the link between tumour mutational profile and response to therapy is critical for identifying targetable vulnerabilities and stratifying patients for therapy.

© 2023. The Author(s).

In plain English

This article is a narrative review, not a new study. The authors summarised published research on the genetics of pleural mesothelioma and its use in treatment. The review did not study asbestos exposure; it named asbestos as a main cause and cited laboratory work showing genetic abnormalities in asbestos-exposed cells. One cited study of 980 pleural mesothelioma samples found CDKN2A alterations in 49% and BAP1 alterations in 44%. The authors described BAP1 tumour predisposition syndrome, an inherited condition in which BAP1 mutation carriers are at high risk of mesothelioma and other cancers. The authors reported that trials targeting these genes' pathways have had modest results. The US Food and Drug Administration has approved a tumour mutational burden cut-off of more than 10 mutations per megabase, measured with the FoundationOne CDx assay, for selecting patients for pembrolizumab. One cited study found a median of 1.74 mutations per megabase in 980 pleural cases; the authors judged this standard definition of little value for selecting mesothelioma patients for immunotherapy. The authors concluded that, with immunotherapy now adopted, identifying and validating markers of treatment response is even more crucial.

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: Narrative review of published research. It is not an original study, and it included no human or animal subjects of its own.
• Who was studied: No study population of its own. The review covered published genetic, gene-expression and clinical-trial studies of pleural mesothelioma.
• Exposure: Asbestos exposure was not studied, and no fiber types are discussed. The authors described asbestos as a main cause of mesothelioma. They briefly cited laboratory work in which cells exposed to asbestos developed genetic abnormalities, including chromosome breakages and aneuploidy. The review's focus is genetic alterations, including CDKN2A, BAP1 and NF2, and inherited BAP1 mutations.
• Main results:
  • In a cited study (Dagogo-Jack and colleagues) of 980 pleural mesothelioma samples, alterations were found in CDKN2A in 49% of cases and in BAP1 in 44%. Other genes altered in 10% or more of cases were CDKN2B (42%), MTAP (34%), NF2 (33%), TP53 (18%) and SETD2 (10%).
  • The authors described BAP1 tumour predisposition syndrome as an inherited (autosomal dominant) condition in which carriers of BAP1 mutations are at high risk of mesothelioma and other cancers, including melanoma.
  • Cited studies reported that patients whose mesothelioma is associated with BAP1 tumour predisposition syndrome have a higher median overall survival, of 5 to 7 years.
  • The authors reported that trials targeting pathways affected by BAP1, CDKN2A and NF2 alterations have had modest results overall.
  • The US Food and Drug Administration has approved a cut-off of more than 10 mutations per megabase, defined by the FoundationOne CDx assay, as a companion biomarker for selecting patients for pembrolizumab immunotherapy.
  • In a cited study using the FoundationOne assay, 980 pleural mesothelioma cases had a median tumour mutational burden of 1.74 mutations per megabase.
  • The authors judged the standard definition of tumour mutational burden to be of little value specifically for selecting mesothelioma patients for immunotherapy.
  • The authors cited an earlier study by their own group in Australian and Danish cohorts. Patients with loss of BAP1 protein expression had significantly longer median survival after first-line pemetrexed and platinum chemotherapy: 19.6 versus 11.1 months in the Australian cohort (p less than 0.01) and 20.1 versus 7.3 months in the Danish cohort (p less than 0.001).
  • PD-L1 expression, which predicts immunotherapy response in lung cancer, was not found to predict response in the mesothelioma trials the authors cited.
• The authors' conclusion: The authors concluded that, with the adoption of immunotherapies, it is even more crucial to identify and validate biomarkers of treatment response.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, CDKN2A, BAP1, Targeted Therapy, Immunotherapy.

Related studies

• Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma — J. Creaney, A.M. Patch, et al. (2022)
• Genomic Landscape of Malignant Mesotheliomas — S. Kato, B.N. Tomson, et al. (2016)
• Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions — D.L. Jardim, S.Z. Millis, et al. (2021)
• Methylation profile landscape in mesothelioma: possible implications in early detection, disease progression, and therapeutic options — X. Zhang, N. Tang, et al. (2015)
• Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma — D. Jean, E. Thomas, et al. (2011)
• Genomics and Functional Genomics of Malignant Pleural Mesothelioma — E. Cakiroglu, S. Senturk (2020)

Browse more research in Current Oncology Reports, or return to medical research.