Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma

Our plain-English summary of Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma, by G.V. Gee, D.C. Koestler, B.C. Christensen, et al (International Journal of Cancer, 2010).

The study

• Authors: G.V. Gee, D.C. Koestler, B.C. Christensen, D.J. Sugarbaker, D. Ugolini, G.P. Ivaldi, M.B. Resnick, E.A. Houseman, K.T. Kelsey, C.J. Marsit
• Journal: International Journal of Cancer
• Published: 2010;127(12):2859-69
• Cited by: 75 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rapidly fatal disease whose diagnosis, particularly through less invasive techniques such as analysis of pleural effusion, can be challenging. Currently, a commercially available diagnostic test based on microRNA (miRNA) expression patterns is purported to distinguish between mesothelioma and lung adenocarcinoma. Yet, the biological basis of this technology has not been reported in the literature, and little research has been aimed at determining how differential miRNA expression contributes to the differences in pathogenesis between these diseases, both of which can be caused by asbestos exposure. We sought to illuminate the molecular differences between mesothelioma and lung adenocarcinoma by using miRNA microarrays to identify patterns in the most differentially expressed miRNAs. From this, we identified a panel of miRNAs, including members of the miR-200 gene family, that were all downregulated in MPM compared to lung adenocarcinoma. Using the more sensitive detection method of quantitative RT-PCR on an independent series of tumors, we validated the specificity of these alterations in 100 MPMs and 32 lung adenocarcinomas. Statistical analysis reveals that these miRNAs exceed the current recommendations for biomarkers and could greatly aid in the differential diagnosis. Further examination led us to predict that they act as redundant regulators of wnt signaling and suggests a role for this pathway in tumor progression. This research points to novel approaches using miRNAs whose decreased expression is unique to mesothelioma as potentially suitable for rapid diagnosis and reveals prospective new targets for the treatment of this deadly disease.

Copyright © 2010 UICC.

In plain English

This laboratory study compared small regulatory molecules called microRNAs in tumors of malignant pleural mesothelioma and lung adenocarcinoma. These two cancers can be hard to tell apart. The article did not report measurements of asbestos exposure. The authors first screened 15 mesothelioma and 10 lung adenocarcinoma biopsies from Genoa, Italy, with microarrays. Seven microRNAs, five of them from the miR-200 family, appeared lower in mesothelioma. The authors then measured these seven in a separate set of 100 mesotheliomas and 32 lung adenocarcinomas. All seven were significantly lower in mesothelioma, from 6-fold lower (miR-203) to 42-fold lower (miR-205). Levels did not differ significantly between epithelioid, sarcomatoid and biphasic mesothelioma. The authors measured how well each microRNA alone separated the tumor types using the area under the curve, where 1 means perfect separation. Values ranged from 0.83 (95% confidence interval 0.74 to 0.92) for miR-200a* to 0.98 (0.97 to 1.00) for miR-200c. A combined model misclassified 10% of the first sample set. Computer predictions suggested these microRNAs act on the wnt signaling pathway. The authors proposed them as biomarkers for telling mesothelioma from lung adenocarcinoma.

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: Laboratory study of human tumor samples: microRNA microarray screening, then confirmation by quantitative RT-PCR in an independent sample set, plus computer-based prediction of the genes these microRNAs target
• Who was studied: Screening set: pleural biopsies from 10 lung adenocarcinoma patients and 15 mesothelioma patients without a defined histological type, from the CREST Biorepository, Genoa, Italy. Validation set: 100 mesothelioma tumor samples and 32 lung adenocarcinoma tumor samples. The mesotheliomas were 23 from Brigham and Women's Hospital (cases from 2005 onward) and 77 from the National Mesothelioma Virtual Bank; by type, 32 uncharacterized, 39 epithelioid, 19 biphasic and 10 sarcomatoid. The adenocarcinomas came from Rhode Island Hospital. Pooled non-diseased lung tissue from 4 donors served as a baseline.
• Exposure: Not reported. The article did not report measurements of asbestos or any other exposure; it compared microRNA levels between two tumor types.
• Main results:
  • In the microarray screen, 4 of 5 miR-200 family members (miR-200c, miR-200b, miR-141, miR-429), plus miR-200a*, miR-203 and miR-205, were lower in mesothelioma than in lung adenocarcinoma.
  • In the original 25 biopsies re-measured by quantitative RT-PCR, the reduction in mesothelioma was statistically significant for six of the seven microRNAs. It was not significant for miR-200a* (p = 0.129 in Table 1).
  • In the independent set (100 mesotheliomas, 32 lung adenocarcinomas), all seven microRNAs were significantly lower in mesothelioma.
  • In the independent set, average levels in mesothelioma compared with lung adenocarcinoma were 6-fold lower (miR-203) to 42-fold lower (miR-205).
  • Levels of these microRNAs did not differ significantly among epithelioid, sarcomatoid and biphasic mesothelioma.
  • In the independent set, miR-200c had the highest area under the curve for separating mesothelioma from lung adenocarcinoma: 0.98 (95% CI 0.97 to 1.00).
  • In the independent set, miR-200a* had the lowest area under the curve of the seven: 0.83 (95% CI 0.74 to 0.92).
  • The authors stated that all seven microRNAs exceeded the International Mesothelioma Interest Group recommendation that a marker have sensitivity or specificity greater than 80%.
  • A combined random forest model was built on the independent set and tested on the original samples. It had a 10% misclassification error (Table 3), with 1 mesothelioma classed as lung adenocarcinoma and 1 lung adenocarcinoma classed as mesothelioma. Random assignment would be expected to give 0.32.
  • Computer target-prediction programs predicted that the reduced microRNAs target several genes in the wnt signaling pathways. This was a prediction and was not tested experimentally.
• The authors' conclusion: The authors proposed that these seven microRNAs could be used as biomarkers to develop a test that detects malignant pleural mesothelioma and helps distinguish it from lung adenocarcinoma. They also proposed that loss of these microRNAs disrupts wnt signaling in mesothelioma.

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: Differential Diagnosis, Pleural Mesothelioma, Pleural Effusion, Mesothelioma, Lung Adenocarcinoma, Asbestos Exposure, Biomarker.

Related studies

• Differential microRNA expression profiling of mesothelioma and expression analysis of miR-1 and miR-214 in mesothelioma — V.J. Amatya, A.S. Mawas, et al. (2016)
• miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer — K.M. Foss, C. Sima, et al. (2011)
• The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma — T. Muraoka, J. Soh, et al. (2013)
• MicroRNAs dysregulation in human malignant pleural mesothelioma — V. Balatti, S. Maniero, et al. (2011)
• Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis — L. Micolucci, M.M. Akhtar, et al. (2016)
• Prognostic and Therapeutic Implications of MicroRNA in Malignant Pleural Mesothelioma — A. Truini, S. Coco, et al. (2016)

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