Molecular changes in mesothelioma with an impact on prognosis and treatment

Our plain-English summary of Molecular changes in mesothelioma with an impact on prognosis and treatment, by D. Jean, J. Daubriac, F. Le Pimpec-Barthes, et al (Archives of Pathology & Laboratory Medicine, 2012).

The study

• Authors: D. Jean, J. Daubriac, F. Le Pimpec-Barthes, F. Galateau-Salle, M.C. Jaurand
• Journal: Archives of Pathology & Laboratory Medicine
• Published: 2012;136(3):277-93
• Type of article: Review
• Cited by: 80 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Context: In recent decades, research on malignant pleural mesothelioma (MPM) has been developed to improve patients' outcomes by increasing the level of confidence in MPM diagnosis and prognosis.

Objective: To summarize data on genetic and epigenetic abnormalities in MPM that may be of interest for a better management of patients with MPM.

Data Sources: Data were obtained from scientific publications on genetic and epigenetic abnormalities in MPM by studying gene mutations, DNA methylation, and gene and microRNA expression profiling.

Conclusions: Molecular changes in MPM consist in altered expression and in activation or inactivation of critical genes in oncogenesis, especially tumor suppressor genes at the INK4 and NF2 loci. Activation of membrane receptor tyrosine kinases and deregulation of signaling pathways related to differentiation, survival, proliferation, apoptosis, cell cycle control, metabolism, migration, and invasion have been demonstrated. Alterations that could be targeted at a global level (methylation) have been recently reported. Experimental research has succeeded especially in abolishing proliferation and triggering apoptosis in MPM cells. So far, targeted clinical approaches focusing on receptor tyrosine kinases have had limited success. Molecular analyses of series of MPM cases have shown that defined alterations are present in MPM subsets, consistent with interindividual variations of molecular alterations, and suggesting that identification of patient subgroups will be essential to develop more specific therapies.

In plain English

This article was a review. The authors summarized published research on genetic and epigenetic changes in malignant pleural mesothelioma, including gene mutations, chromosome changes, DNA methylation, and gene and microRNA expression, and their possible use for diagnosis, prognosis and treatment. They described findings from other studies. At the CDKN2A gene locus, the most frequent alteration was homozygous deletion, in about 70% of cases, and this deletion was reported as a significant independent adverse prognostic factor. NF2 inactivation rates ranged from 20% to 60%, TP53 mutation frequency was about 20%, and no recurrent oncogene mutation had been identified. On asbestos, reviewed studies reported correlations between high asbestos fiber content in lung tissue and losses of chromosomes 1, 4 and 9. They also reported a correlation between methylation of the RASSF1 gene and the number of asbestos bodies in the lung. Targeted drugs against receptor tyrosine kinases had shown limited success. The authors concluded that molecular changes vary between patients and that identifying patient subgroups would be essential to develop more specific therapies. They noted that many results still needed confirmation in larger numbers of cases.

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 studies
• Who was studied: Published studies on genetic and epigenetic abnormalities in malignant pleural mesothelioma (tumors, cell lines and some animal models); no new patients studied
• Exposure: Not an exposure study; the review summarizes molecular changes in mesothelioma, including some studies comparing asbestos-exposed and nonexposed patients
• Main results:
  • Reviewed studies: at the CDKN2A locus, the most frequent alteration was homozygous deletion, in about 70% of cases (CDKN2A deletion is described as one of the most frequent alterations in MPM)
  • Reviewed studies: homozygous CDKN2A deletion detected by FISH was reported as a significant independent adverse prognostic factor
  • Reviewed studies: NF2 inactivation rates ranged from 20% to 60%, depending on material and method
  • Reviewed studies: TP53 mutation frequency in human MPM was about 20%
  • Reviewed studies: no recurrent oncogene mutation had been identified in MPM
  • Reviewed studies: high asbestos fiber content in lung tissue was correlated with partial or total losses of chromosomes 1, 4 and 9
  • Reviewed study: of the tumor suppressor gene loci examined, only RASSF1 methylation correlated with an increased number of asbestos bodies in the lung
  • Reviewed phase II trials of EGFR inhibitors: response rates of 0% to 4% and median overall survival of 4.6 to 13.1 months
  • Reviewed clinical trials: the PDGFR inhibitor imatinib mesylate was ineffective
• The authors' conclusion: The authors concluded that mesothelioma shows heterogeneity at the genome and gene levels, and that identifying patient subgroups would be essential to develop more specific therapies
• Limitations the authors state:
  • Gene expression findings needed confirmation in larger numbers of cases before clinical use
  • Laboratory studies used MPM specimens that may not share the genomic status of patients' tumors
  • Some microarray-based survival predictors were less accurate than usual clinicopathologic prognosis

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Pleural Mesothelioma, Oncogenesis, Tumor Suppressor Gene, Apoptosis.

Related studies

• Molecular and genetic changes in asbestos-related lung cancer — P. Nymark, H. Wikman, et al. (2008)
• The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment — V. Galani, A. Varouktsi, et al. (2019)
• MGMT promoter methylation is a rare epigenetic change in malignant effusions — M. Brunetti, I. Panagopoulos, et al. (2020)
• ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma — Y.Y. Cheng, M.B. Kirschner, et al. (2013)
• Asbestos-associated genome-wide DNA methylation changes in lung cancer — E. Kettunen, H. Hernandez-Vargas, et al. (2017)
• Chromosomal changes induced by chrysotile fibres or benzo-3,4-pyrene in rat pleural mesothelial cells — M.C. Jaurand, L. Kheuang, et al. (1986)

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