Molecular biology of malignant mesothelioma

Our plain-English summary of Molecular biology of malignant mesothelioma, by Y. Sekido (Environmental Health and Preventive Medicine, 2008).

The study

• Author: Y. Sekido
• Journal: Environmental Health and Preventive Medicine
• Published: 2008;13(2):65-70
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Human malignancies develop via a multi-step that involves the accumulation of several key gene alterations with associated genetic and epigenetic events. Although malignant mesothelioma (MM) has been demonstrated to be clearly correlated with asbestos exposure, it remains poorly understood how asbestos fibers confer key gene alterations and induce cellular transformation in normal mesothelial cells, which results in the acquisition of malignant phenotypes, including deregulated cell proliferation and invasion. Malignant mesothelioma presents with the frequent inactivation of tumor suppressor genes of p16(INK4a)/p14(ARF) on chromosome 9p21 and neurofibromatosis type 2 (NF2) on chromosome 22q12, with the latter being responsible for the NF2 familial cancer syndrome. In contrast, MM shows infrequent mutation of the p53 gene, which is one of the most frequently mutated tumor suppressor genes in human malignancies. Genetic abnormalities of oncogenes have also been studied in MM, but no frequent mutations have been identified, including the epidermal growth factor receptor (EGFR) and K-RAS genes. Recent studies have suggested the activation of other receptor tyrosine kinases, including Met, and the deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, although the alterations responsible for their activation are still not clear. Thus, further genome-wide studies of genetic and epigenetic alterations as well as detailed analyses of deregulated signaling cascades in MM are necessary to determine the molecular mechanisms of MM, which would also provide some clues for establishing a new molecular target therapy for MM.

In plain English

This article was a narrative review by the author, based on a symposium lecture given in Osaka, Japan, in 2007. It covered published research on the molecular biology of malignant mesothelioma, mostly malignant pleural mesothelioma, and did not report new data. The author summarized proposed ways asbestos fibers might cause the disease. The author noted that it had not yet been clearly determined whether the fibers act on mesothelial cells directly or indirectly. Citing earlier studies, the review reported that most pleural mesotheliomas showed frequent inactivation of the p16INK4a/p14ARF genes, that only 20–25% showed a p53 mutation, and that about 40% showed an NF2 gene mutation. One cited study found EGFR overexpressed in 56% of primary tumors, with no EGFR mutation found. The author described the role of the SV40 virus as controversial and said that the molecular targeted therapies tested so far had not given satisfactory results. The author concluded that further genome-wide studies and detailed analyses of signaling pathways were needed to understand how mesothelioma develops. The author noted that many observations could not be cited because of restrictions on the preparation of review manuscripts.

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 (based on a symposium lecture); no new data
• Who was studied: No study population of its own. The author reviewed published research on human malignant mesothelioma (mainly pleural), mesothelioma cell lines and animal models. The article was based on a lecture at the 77th Annual Meeting of the Japanese Society for Hygiene, Osaka, March 2007.
• Exposure: Asbestos in general. The six types listed are amosite, crocidolite, anthophyllite, actinolite, tremolite and chrysotile. The cited laboratory work used crocidolite and chrysotile in rat pleural mesothelial cells.
• Main results:
  • The author stated that it had not yet been clearly determined whether asbestos fibers act directly on mesothelial cells or cause mesothelioma indirectly. Several proposed mechanisms were described.
  • From cited studies of malignant pleural mesothelioma (MPM): most cases show frequent inactivation of p16INK4a/p14ARF, and only 20–25% show a mutation of p53.
  • From cited studies: about 40% of MPMs showed a mutation of the NF2 gene. The review stated that, in total, 50–60% of MPMs showed inactivation of NF2.
  • From a cited study: EGFR was overexpressed in 56% of primary tumors, but no EGFR mutation was documented.
  • From a cited study: an activated N-RAS mutation was found in three of 38 mesotheliomas.
  • The author described the involvement of the SV40 virus in malignant mesothelioma as controversial. Positive results in earlier studies may have been false positives caused by laboratory plasmid contamination.
  • Several molecular targeted therapies had been tested in mesothelioma without satisfactory results to date.
• The authors' conclusion: The author concluded that further genome-wide studies of genetic and epigenetic alterations and detailed analyses of deregulated signaling pathways are necessary to determine the molecular mechanisms of mesothelioma. The author added that this could give clues for new targeted therapy.
• Limitations the authors state:
  • The author stated that many relevant observations were not cited because of restrictions on the preparation of review manuscripts.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Asbestos Exposure, Mesothelial Cells, Tumor Suppressor Gene, EGFR.

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