Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

Our plain-English summary of Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge, by D.M. Abbott, C. Bortolotto, S. Benvenuti, et al (Cancers, 2020).

The study

• Authors: D.M. Abbott, C. Bortolotto, S. Benvenuti, A. Lancia, A.R. Filippi, G.M. Stella
• Journal: Cancers
• Published: 2020;12(5)
• Type of article: Review
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches.

In plain English

This article is a narrative review; it did not study new patients. It summarized published research on malignant pleural mesothelioma (MPM), a cancer of the lining around the lungs, focusing on the tumor's genetics and the inflammation around it. Drawing on other studies, the review stated that at least 80% of cases are caused by asbestos fibers. It said the International Agency for Research on Cancer classifies both chrysotile and amphibole fibers (such as crocidolite, amosite and tremolite) as Class I carcinogens, and that no safe lower exposure threshold has been identified. It cited WHO data recording nearly 100,000 MPM deaths in 83 countries from 1994 to 2008, and gave median survival as around 13 to 15 months after diagnosis. It described frequent changes in the CDKN2A, NF2 and BAP1 genes, BAP1 mutations that may increase susceptibility, and asbestos-triggered inflammation involving the protein HMGB1. It noted that many targeted drugs had failed. The authors concluded that growing evidence suggests asbestos-induced inflammation might cause mesothelial cells to become malignant, and that no actionable targets currently exist for effective treatment.

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
• Who was studied: No new study population. The review covered published studies on malignant pleural mesothelioma, including human tumor samples, patient cohorts, clinical trials, cell experiments and animal models. The authors are from the University of Pavia and the Candiolo Cancer Institute, Italy.
• Exposure: Asbestos fibers in general: chrysotile (serpentine) and amphiboles (crocidolite, amosite, tremolite). The review also mentioned erionite, fluoro-edenite, radiation therapy and other suspected agents. No doses were studied.
• Main results:
  • Citing earlier work, the review stated that at least 80% of MPM cases are caused by asbestos exposure.
  • The review reported that IARC classifies both chrysotile and amphibole fibers as Class I carcinogens.
  • According to IARC and WHO, as cited by the review, no safe lower exposure threshold has been identified.
  • Citing WHO mortality data, the review reported nearly 100,000 MPM deaths in 83 countries from 1994 to 2008, about 5 deaths per million.
  • The review attributed the still-rising incidence to a 20 to 40 year latency of asbestos effects.
  • The review gave median survival for MPM as around 13 to 15 months after diagnosis.
  • Reviewed genetic studies found the most frequently altered chromosome areas in MPM to be CDKN2A at 9p21 and NF2 at 22q12.
  • The review reported that roughly 40% of mesotheliomas have an NF2 mutation.
  • The review reported that genetic analysis suggests BAP1 mutations may increase susceptibility, including in families with several mesothelioma cases.
  • The review described the protein HMGB1 as a key driver of the chronic inflammation behind mesothelioma growth.
  • The review reported that guideline first-line therapy is pemetrexed with cisplatin, possibly with bevacizumab.
  • The review reported that modern targeted therapies have so far failed in MPM.
• The authors' conclusion: The authors concluded that no actionable targets are currently available to treat MPM effectively. They also concluded that growing evidence suggests asbestos-induced inflammation might cause the malignant transformation of mesothelial cells.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Peritoneum, Pleura, Pericardium, Tunica Vaginalis, Malignant Mesothelioma, Mineral Fiber.

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• Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas — J.M. Sands, T. Nguyen, et al. (2020)
• The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer — L.H. Matherly, Z. Hou, et al. (2018)
• Diagnostic and Therapeutic Challenges of Malignant Pleural Mesothelioma — J. Moro, S. Sobrero, et al. (2022)
• Immune checkpoint inhibitors a new player in the therapeutic game of mesothelioma: New reality with new challenges — K. Parikh, L.E.L. Hendriks, et al. (2021)
• Malignant pleural mesothelioma: a therapeutic challenge — G. Dimitrakakis, T. BinEsmael, et al. (2011)

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