Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations

Our plain-English summary of Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations, by E. Lorenzini, A. Ciarrocchi, F. Torricelli (Journal of Clinical Medicine, 2021).

The study

• Authors: E. Lorenzini, A. Ciarrocchi, F. Torricelli
• Journal: Journal of Clinical Medicine
• Published: 2021;10(11)
• Type of article: Review
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.

In plain English

This article was a narrative review, not a new study. The authors, from a translational research laboratory in Reggio Emilia, Italy, drew on literature from early mesothelioma research up to early 2021 (121 references). They examined the epigenome in malignant pleural mesothelioma (MPM): the chemical controls that switch genes on and off without changing the DNA sequence. The review discussed asbestos exposure in general and did not separate fiber types. Citing earlier sequencing studies, it reported that MPM carries few mutations, that BAP1 is inactivated in about 57% of cases and NF2 in 40–50%, and that no asbestos-associated mutational signature had been identified. It described a study of 158 mesothelioma specimens that found DNA methylation status correlated positively with asbestos exposure. It also reviewed blood-based markers, noting that one study found microRNAs failed to detect cancer in samples taken before diagnosis. A cited phase III trial of vorinostat observed no significant improvement in overall survival compared with placebo. The authors concluded that epigenetic drugs might offer a new treatment approach if combined with chemotherapy or other drugs.

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 literature on epigenetics in malignant pleural mesothelioma
• Who was studied: Published literature from early mesothelioma research through early 2021, 121 references; no new patients studied
• Exposure: Chronic asbestos exposure in general; the review does not distinguish fiber types (chrysotile, amphiboles, etc.)
• Main results:
  • Citing earlier genomic studies, the review reported that MPM has a low mutational burden, with a mean of fewer than 2 somatic non-synonymous mutations per megabase
  • Citing earlier studies, the review reported that no asbestos-associated mutational signature had been identified in MPM
  • Citing deep mutational profiling, the review reported BAP1 inactivation in about 57% of MPM cases
  • The review reported NF2 inactivation in 40–50% of MPM cases, citing earlier studies
  • Christensen et al., cited in the review, compared methylation of 803 genes in 158 mesothelioma specimens with 18 normal pleura samples and found a positive correlation between methylation status and asbestos exposure
  • A cited study compared blood DNA methylation in 163 MPM patients with 137 healthy controls and found more than 800 differentially methylated sites
  • Weber and colleagues, cited in the review, found that circulating microRNAs in prediagnostic plasma samples failed to detect cancer
  • A cited phase II trial of valproic acid with doxorubicin observed a partial response in 6 of 45 second-line MPM patients
  • A cited phase III randomized, placebo-controlled trial of vorinostat (SAHA) in second- and third-line MPM patients observed no significant improvement in overall survival
• The authors' conclusion: The authors concluded that single-agent epigenetic drugs have shown poor applicability in solid cancers, but that combined with chemotherapy or other drugs they may represent a new therapeutic perspective for MPM
• Limitations the authors state:
  • The authors note that the circulating microRNA studies they reviewed used cross-sectional cohorts of mostly late-stage patients, leaving early diagnosis untested
  • The authors state that larger and more homogeneous patient cohorts are needed to define the value of blood methylation markers

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Silicate.

Related studies

• Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma — O.D. Røe, A. Szulkin, et al. (2012)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival — L. Quetel, C. Meiller, et al. (2020)
• Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma — S. Hiltbrunner, L. Mannarino, et al. (2021)
• Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma — B.C. Christensen, E.A. Houseman, et al. (2010)
• Genetic alterations in cancer knowledge system: analysis of gene mutations in mouse and human liver and lung tumors — M.A. Jackson, I. Lea, et al. (2006)

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