Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy

Our plain-English summary of Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy, by M. Tomasetti, M. Amati, J. Neuzil, et al (Lung Cancer, 2017).

The study

• Authors: M. Tomasetti, M. Amati, J. Neuzil, L. Santarelli
• Journal: Lung Cancer
• Published: 2017;107:65-72
• Type of article: Review
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Lung cancer (LC) and malignant mesothelioma (MM) are malignancies linked to environmental/occupational exposure, which are increasing in incidence. Despite advances in chemotherapy, radiation therapy and surgical management of LC and MM, the median survival remains less than 12 months. Early detection represents one of the most promising approaches to reducing the growing cancer burden by increasing chemotherapy treatment efficiency. At present, early diagnosis is rather difficult and depends on invasive sampling of pleural fluid or tissue. Currently the most widely used screening method for the surveillance of exposed subjects is computed tomography (CT), which is costly, exposes patients to repeated high doses of radiation, and typically detects the malignancy at its advanced stage. Recently, a virtually non-invasive 'liquid biopsy' has emerged as source to characterize tumour heterogeneity. The genetic/epigenetic changes during tumour evolution can be detected in fluids and used as cancer biomarkers. Therefore, increasingly interest has been paid to circulating (cell-free) nucleic acids (cfDNA/cfmiRNAs) epigenetically modulated during cell transformation. Hypermethylation of tumour suppressor genes is frequently observed in cancers, and such epigenetic changes are potential markers for detecting and monitoring tumours. The same predictive biomarkers can be used as therapy targets.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This article is a review, not a new study. The authors summarized published research on blood-based ('liquid biopsy') epigenetic markers for lung cancer and malignant mesothelioma, and on epigenetic-based treatments. They described asbestos as one of several agents that can cause epigenetic changes. They cited earlier work linking RASSF1 methylation in mesothelioma to higher asbestos body counts. For mesothelioma, they reported earlier blood-marker results. miR-126 alone showed 75% sensitivity but 54% specificity. In distinguishing mesothelioma patients from healthy controls, the protein marker SMRP showed 60-70% sensitivity and 90-100% specificity; it worked less well for sarcomatoid or early-stage disease. Methylated thrombomodulin DNA distinguished patients from controls with 82% specificity but 60% sensitivity. A prior study by Santarelli, one of this review's authors, and colleagues combined these three markers into one model. Treatment research described came mostly from pre-clinical and mouse studies; one miR-34 drug had entered a phase I trial. The authors concluded that no single biomarker with reasonable sensitivity and specificity had yet been described. They suggested that combining markers of different molecular classes might improve performance.

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 study population of its own. The authors reviewed published studies on lung cancer and malignant mesothelioma, including studies of patients, healthy controls, asbestos-exposed subjects and animal models.
• Exposure: Not an exposure study. Asbestos is discussed as one of several toxic agents that can cause epigenetic changes. No fiber types are named.
• Main results:
  • Cited earlier work (reference 35): RASSF1 methylation was found in 33% of malignant mesothelioma cases and was significantly associated with increased asbestos body count.
  • Cited earlier work (reference 30): an asbestos-associated microRNA signature was identified in lung cancer.
  • Cited earlier work: in malignant mesothelioma, blood miR-126 alone predicted the disease with 75% sensitivity but 54% specificity.
  • Cited earlier work: SMRP levels distinguished malignant mesothelioma patients from healthy controls with 60-70% sensitivity and 90-100% specificity.
  • Cited earlier work: SMRP separated controls from patients with advanced epithelioid or biphasic malignant mesothelioma better than from patients with sarcomatoid or early-stage disease.
  • Cited earlier work: a meta-analysis found that in symptomatic or high-risk subjects, a negative SMRP blood test did not exclude malignant mesothelioma.
  • Cited earlier work (reference 73, by Santarelli and colleagues; Santarelli is an author of this review): circulating methylated thrombomodulin (TM) DNA distinguished malignant mesothelioma patients from controls with 82% specificity and 60% sensitivity. It was reported to complement miR-126 and SMRP in a 3-biomarker model.
  • Cited earlier work: miR-625-3p distinguished malignant mesothelioma patients from healthy individuals with 73% sensitivity, 79% specificity and 82% overall accuracy.
  • Cited earlier work: miR-103a-3p combined with SMRP gave an AUC of 0.93, with 95% sensitivity and 81% specificity. The authors noted that this miRNA was measured in the cellular fraction of blood, not plasma.
  • Treatment research described was largely pre-clinical, including mouse models. A liposome-based miR-34 mimic (MRX34) had entered a phase I clinical trial.
• The authors' conclusion: The authors concluded that no single biomarker with reasonable sensitivity and specificity had yet been described for lung malignancies. They suggested that combining biomarkers of different molecular classes, including cell-free DNA/RNA, might improve performance.
• Limitations the authors state:
  • The authors stated that the protein biomarkers conventionally used for lung cancer and malignant mesothelioma lack satisfactory specificity and reliability. This is a limitation of the evidence reviewed, not of the review itself.
  • The authors stated that technical challenges remain for microRNA-based therapies.

Topics

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

Medical terms in this study, explained in our Lexicon: Biomarker, Lung Cancer, Malignant Mesothelioma, Occupational Exposure, Chemotherapy, Median Survival, Liquid Biopsy.

Related studies

• Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma — L. Santarelli, S. Staffolani, et al. (2015)
• A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma — B.T.V. Duong, L. Wu, et al. (2020)
• Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy — M. Tomasetti, S. Gaetani, et al. (2019)
• Are circulating microRNAs suitable for the early detection of malignant mesothelioma? Results from a nested case-control study — D.G. Weber, A. Brik, et al. (2019)
• Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma — H. Sato, J. Soh, et al. (2019)
• ATG5 as biomarker for early detection of malignant mesothelioma — M. Tomasetti, F. Monaco, et al. (2023)

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