Molecular pathogenesis of malignant mesothelioma

Our plain-English summary of Molecular pathogenesis of malignant mesothelioma, by Y. Sekido (Carcinogenesis, 2013).

The study

• Author: Y. Sekido
• Journal: Carcinogenesis
• Published: 2013;34(7):1413-9
• Type of article: Review
• Cited by: 191 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive tumor arising primarily from the pleural or peritoneal cavities. It develops by asbestos exposure after a long latency, which is characterized by insidious growth and clinical presentation at an advanced stage of disease. MM is highly refractory to conventional therapies even with a combination of aggressive surgical intervention and multimodality strategies, with cure remaining elusive. Molecular genetic analysis has revealed several key genetic alterations, which are responsible for the development and progression of MM. The cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF), neurofibromatosis type 2 (NF2) and BRCA1-associated protein-1 (BAP1) genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM. Merlin, which is encoded by NF2, regulates multiple cell signaling cascades including the Hippo and mammalian target of rapamycin pathways, which regulate cell proliferation and growth. BAP1 is involved in histone modification and its inactivation induces the disturbance of global gene expression profiling. The discovery of a new familial cancer syndrome with germline mutation of BAP1 also indicates the importance of genetic factors in MM susceptibility. Meanwhile, although frequent expression and functional activations of oncogene products such as receptor tyrosine kinases are observed in MM cells, activating mutations of these genes are rare. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them will be applied for developing new diagnostic tools and new target therapies against MMs.

In plain English

This article is a review by a single author, not a new study. It summarized published research on how malignant mesothelioma develops at the molecular level. It focused on changes caused by asbestos and on three tumor suppressor genes: CDKN2A/ARF, NF2 and BAP1. The review noted that over 80% of mesothelioma patients have a history of asbestos exposure, that crocidolite is considered the most carcinogenic type of asbestos, and that erionite also causes mesothelioma. Citing earlier studies, it reported several gene-change rates. Homozygous deletion of CDKN2A/ARF was found in over 70% of cases examined by FISH, a laboratory test. Inactivating NF2 mutations were found in 40–50% of cases. One study found a somatic BAP1 mutation in 12 (23%) of 53 cases. Inherited (germline) BAP1 mutations had been found in two families with a high incidence of mesothelioma. Because fewer than 5% of asbestos workers develop mesothelioma, the author concluded that differences in individual susceptibility at similar exposure levels need to be determined more precisely.

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 on the molecular pathogenesis of malignant mesothelioma
• Who was studied: No new population was studied. The review drew on published studies of human malignant mesothelioma (pleural and peritoneal) tissues and cell lines, and on animal models.
• Exposure: Asbestos in general: the amphiboles (amosite, crocidolite, anthophyllite, actinolite, tremolite) and the serpentine chrysotile. Also erionite, and multiwalled carbon nanotubes in experimental studies.
• Main results:
  • The review stated that over 80% of mesothelioma patients have a history of asbestos exposure.
  • In published FISH analyses of mesothelioma tissue or pleural effusion cells, over 70% of cases showed homozygous deletions of CDKN2A/ARF.
  • In published studies, 40–50% of mesothelioma cases had an inactivating NF2 mutation.
  • In one cited study (Bott et al.), 12 (23%) of 53 mesothelioma cases had a somatic BAP1 mutation.
  • Germline BAP1 mutations were detected in two families with a high incidence of mesothelioma.
  • Activating mutations in oncogenes such as epidermal growth factor receptor families, K-Ras and PIK3CA were reported to be rare in mesothelioma.
  • In a cited mouse study, asbestos-exposed Nf2 (+/−) knockout mice developed mesothelioma markedly faster than asbestos-treated normal littermates.
  • In a cited experimental study, thin multiwalled carbon nanotubes pierced mesothelial cell membranes and were toxic to the cells in laboratory tests.
  • The review stated that fewer than 5% of asbestos workers develop mesothelioma, which it took to suggest differences in genetic susceptibility.
• The authors' conclusion: The author concluded that differences in individual susceptibility to mesothelioma among people with asbestos exposures of similar level and duration need to be determined more precisely to establish a more effective preventive strategy.
• Limitations the authors state:
  • The reviewed studies used methods with different sensitivity and specificity, and defined mutations such as 'homozygous deletion' differently.
  • Not all relevant work could be cited because of space limitations.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Asbestos Exposure, Latency, CDKN2A, BAP1, Tumor Suppressor Gene, Merlin, Discovery.

Related studies

• Loss of BAP1 function leads to EZH2-dependent transformation — L.M. LaFave, W. Béguelin, et al. (2015)
• Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma — C. Glass, L.M. Sholl, et al. (2020)
• A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair — R. Parrotta, A. Okonska, et al. (2017)
• Connecting molecular pathways to hereditary cancer risk syndromes — J.R. Testa, D. Malkin, et al. (2013)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)
• Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma — M. Hylebos, K. Op de Beeck, et al. (2018)

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