Genomics and Epigenetics of Malignant Mesothelioma

Our plain-English summary of Genomics and Epigenetics of Malignant Mesothelioma, by A.P. Sage, V.D. Martinez, B.C. Minatel, et al (High-throughput, 2018).

The study

• Authors: A.P. Sage, V.D. Martinez, B.C. Minatel, M.E. Pewarchuk, E.A. Marshall, G.M. MacAulay, R. Hubaux, D.D. Pearson, A.A. Goodarzi, G. Dellaire, W.L. Lam
• Journal: High-throughput
• Published: 2018;7(3)
• Type of article: Review
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive and lethal asbestos-related disease. Diagnosis of malignant mesothelioma is particularly challenging and is further complicated by the lack of disease subtype-specific markers. As a result, it is especially difficult to distinguish malignant mesothelioma from benign reactive mesothelial proliferations or reactive fibrosis. Additionally, mesothelioma diagnoses can be confounded by other anatomically related tumors that can invade the pleural or peritoneal cavities, collectively resulting in delayed diagnoses and greatly affecting patient management. High-throughput analyses have uncovered key genomic and epigenomic alterations driving malignant mesothelioma. These molecular features have the potential to better our understanding of malignant mesothelioma biology as well as to improve disease diagnosis and patient prognosis. Genomic approaches have been instrumental in identifying molecular events frequently occurring in mesothelioma. As such, we review the discoveries made using high-throughput technologies, including novel insights obtained from the analysis of the non-coding transcriptome, and the clinical potential of these genetic and epigenetic findings in mesothelioma. Furthermore, we aim to highlight the potential of these technologies in the future clinical applications of the novel molecular features in malignant mesothelioma.

In plain English

This article is a review, not a new study. The authors summarized published research that used high-throughput genetic and epigenetic technologies to study malignant mesothelioma. They also described public data resources such as The Cancer Genome Atlas mesothelioma cohort of 87 malignant pleural mesothelioma cases. The studies they reviewed reported that BAP1 was the most frequently altered gene, with one recent analysis suggesting alterations in up to 57% of samples. CDKN2A deletion was reported in up to 80% of pleural mesothelioma cases but in 25% of peritoneal cases. Reviewed work also reported that mutational patterns did not differ significantly between cases with or without known asbestos exposure, and that chrysotile and crocidolite changed DNA methylation differently in a mesothelial cell line. Inherited BAP1 mutations and other gene variants were linked to mesothelioma risk. The review also covered microRNAs and long non-coding RNAs as possible diagnostic and prognostic markers. The authors concluded that these technologies had improved understanding of mesothelioma but had revealed only a fraction of its molecular alterations. They noted that many findings still needed confirmation in other cohorts.

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 genomic, epigenomic and non-coding RNA research on malignant mesothelioma, plus a description of public data resources
• Who was studied: Published studies and public datasets on mesothelioma tissues, blood samples and cell lines, including The Cancer Genome Atlas mesothelioma (TCGA-MESO) cohort of 87 malignant pleural mesothelioma cases
• Exposure: Asbestos in general, as the main cause discussed. One reviewed cell-line study compared chrysotile and crocidolite exposure of mesothelial cells (Met5A).
• Main results:
  • A recent analysis cited by the review (TCGA-MPM) suggested BAP1 alterations in up to 57% of malignant pleural mesothelioma samples. The authors described BAP1 as the most frequently altered gene in mesothelioma.
  • Sources cited by the review reported CDKN2A deletion in up to 80% of pleural mesothelioma cases, more often in sarcomatoid tumors, and in 25% of peritoneal mesothelioma cases.
  • A reviewed study found that mutational signatures in mesothelioma were not significantly different between cases with and without known asbestos exposure.
  • In a reviewed study of pleural effusion samples, MTAP immunohistochemistry alone had a sensitivity of 42.2% for distinguishing malignant from benign mesothelial growths. Combined with BAP1 immunohistochemistry, sensitivity rose to 77.8%.
  • The review reported that the NF2 gene is inactivated by mutation in about 40% of malignant mesothelioma.
  • A reviewed genome-wide association study of 407 pleural mesothelioma cases and 389 controls with asbestos exposure histories found an increased risk linked to abnormalities in chromosomal region 7p22.2.
  • A reviewed Western Australian study (428 cases and 1269 controls) found variants in the CRTAM, SDK1 and RASGRF2 genes significantly associated with malignant mesothelioma risk.
  • Reviewed studies reported that microRNAs of the miR-200 family could help distinguish malignant mesothelioma from lung adenocarcinoma.
• The authors' conclusion: The authors concluded that high-throughput technologies had improved understanding of the genomic and epigenomic factors in malignant mesothelioma. They added that the results so far cover only a fraction of the disease's molecular alterations.
• Limitations the authors state:
  • Multi-gene signatures for identifying mesothelioma had not yet been tested in other samples or cohorts.
  • MicroRNA studies were limited by their sample sources and sizes and by analyzing only a limited number of microRNAs.
  • The few genome-wide association studies available only suggested that genetic background modifies the effect of asbestos. They did not show that it directly confers differing susceptibility.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Fibrosis, Mesothelioma, Prognosis.

Related studies

• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Discovery of Previously Undetected MicroRNAs in Mesothelioma and Their Use as Tissue-of-Origin Markers — V.D. Martinez, E.A. Marshall, et al. (2019)
• Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome — B.C. Christensen, E.A. Houseman, et al. (2009)
• Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance — K. Olino, T. Park, et al. (2020)
• Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma — L. Santarelli, S. Staffolani, et al. (2015)
• Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma — B.C. Christensen, E.A. Houseman, et al. (2010)

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