Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation

Our plain-English summary of Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation, by L. Ferrari, M. Carugno, C. Mensi, et al (Frontiers in Oncology, 2020).

The study

• Authors: L. Ferrari, M. Carugno, C. Mensi, A.C. Pesatori
• Journal: Frontiers in Oncology
• Published: 2020;10:445
• Type of article: Review
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, which originates from the mesothelial cells of the pleura and is associated with asbestos exposure. In light of its aggressive nature, late diagnosis and dismal prognosis, there is an urgent need for identification of biomarkers in easily accessible samples (such as blood) for early diagnosis of MPM. In the last 10 years, epigenetic markers, such as DNA methylation and microRNAs (miRNAs), have gained popularity as possible early diagnostic and prognostic biomarkers in cancer research. The aim of this review is to provide a critical analysis of the current evidences on circulating epigenetic biomarkers for MPM and on their translational potential to the clinical practice for early diagnosis and for prognosis.

Copyright © 2020 Ferrari, Carugno, Mensi and Pesatori.

In plain English

This article is a review by four authors from Milan, Italy, of published research on blood-based ("circulating") epigenetic markers, mainly DNA methylation and microRNAs, for diagnosing malignant pleural mesothelioma early or predicting its outcome. It reports no new data, and it does not describe how the studies were found or chosen. The authors noted that very few studies had examined DNA methylation in blood. Several microRNA studies they reviewed reported differences between mesothelioma patients and asbestos-exposed or unexposed people. For example, a study by the authors' own group of 23 patients and 19 cancer-free people with past asbestos exposure reported a two-microRNA signature with 95.5% sensitivity and 80% specificity. However, one study used blood taken before diagnosis from 17 cases in a German cohort of asbestos-exposed workers. It found that none of the microRNAs tested differed between cases and controls. The authors pointed to small, mostly cross-sectional studies of late-stage patients and unstandardized laboratory methods. They concluded that no currently available marker is reliable enough for monitoring asbestos-exposed people or for early diagnosis, and they called for large validation studies.

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 (no new data)
• Who was studied: Published studies of blood (serum, plasma or blood cell) epigenetic markers in malignant pleural mesothelioma patients and comparison groups (asbestos-exposed people, unexposed healthy people, people with asbestosis or other diseases). The article does not describe a search method or selection criteria for the studies.
• Exposure: The markers reviewed were circulating DNA methylation, microRNA expression, and combinations with proteins such as mesothelin and with long non-coding RNAs. Asbestos exposure was not itself measured. Many of the reviewed studies used asbestos-exposed people as controls.
• Main results:
  • One reviewed study (Fischer et al., serum DNA of 43 patients with pleural and peritoneal mesothelioma) reported that combined hypermethylation of RARβ, DAPK and RASSF1A was associated with shorter overall survival.
  • One reviewed study (Santarelli et al.) reported reduced serum miR-126 in mesothelioma patients. The authors described its ability to tell groups apart as moderate: sensitivity 60% and specificity 74% compared with asbestos-exposed subjects, and sensitivity 73% and specificity 74% compared with unexposed healthy controls.
  • The authors' own earlier study (Cavalleri et al.), in 23 mesothelioma patients and 19 cancer-free subjects with past asbestos exposure, reported that a two-microRNA signature (miR-103a-3p and miR-30e-3p) in plasma extracellular vesicles told the groups apart with 95.5% sensitivity and 80% specificity.
  • A reviewed nested case-control study (Weber et al. 2019) used blood collected before diagnosis from 17 mesothelioma cases in a German cohort of asbestos-exposed workers, each matched with two cancer-free controls. None of the three microRNAs analyzed differed between the groups. With a high-specificity cut-off, none of the cases was detected.
  • Among reviewed studies combining markers, mesothelin plus miR-103a-3p (43 mesothelioma patients, 52 asbestos-exposed individuals) showed 95% sensitivity and 81% specificity. Another combination (miR-126, methylated thrombomodulin and SMRPs) only slightly improved on SMRPs alone.
• The authors' conclusion: The authors concluded that none of the currently available markers is reliable enough for surveillance of asbestos-exposed people or for early diagnosis of malignant pleural mesothelioma. They called for large validation studies focused on early-stage disease, with standardized methods.
• Limitations the authors state:
  • The authors noted that most of the reviewed microRNA studies were cross-sectional and involved late-stage patients, which leaves their value for early diagnosis open.
  • The authors noted that differing laboratory methods, platforms and normalization strategies in the reviewed studies hamper reproducibility.
  • The authors noted that some microRNAs, such as miR-126, have also been linked to other cancers and non-cancer conditions, so they may not be specific to mesothelioma.
  • The authors noted that biological factors greatly limit the use of circulating DNA methylation as a diagnostic marker.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, State-of-the-Art Defense, Mesothelial Cells, Pleura, Asbestos Exposure, Prognosis.

Related studies

• Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy — M. Tomasetti, M. Amati, et al. (2017)
• Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma — L. Santarelli, S. Staffolani, et al. (2015)
• Epigenetic investigation into circulating microRNA 197-3p in sera from patients affected by malignant pleural mesothelioma and workers ex-exposed to asbestos — G. Di Mauro, F. Frontini, et al. (2023)
• Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy — M. Tomasetti, S. Gaetani, et al. (2019)
• Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment — Y. Yoshikawa, K. Kuribayashi, et al. (2020)
• SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma — Y.Y. Cheng, E. Mok, et al. (2017)

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