A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma

Our plain-English summary of A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma, by H. Benjamin, D. Lebanony, S. Rosenwald, et al (The Journal of Molecular Diagnostics, 2010).

The study

• Authors: H. Benjamin, D. Lebanony, S. Rosenwald, L. Cohen, H. Gibori, N. Barabash, K. Ashkenazi, E. Goren, E. Meiri, S. Morgenstern, M. Perelman, I. Barshack, Y. Goren, T.B. Edmonston, A. Chajut, R. Aharonov, Z. Bentwich, N. Rosenfeld, D. Cohen
• Journal: The Journal of Molecular Diagnostics
• Published: 2010;12(6):771-9
• Cited by: 86 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The definitive identification of malignant pleural mesothelioma (MPM) has significant clinical implications, yet other malignancies often involve the lung pleura, confounding the diagnosis of MPM. In the absence of accurate markers, MPM can be difficult to distinguish from peripheral lung adenocarcinoma and metastatic epithelial cancers. MicroRNA expression is tissue-specific and highly informative for identifying tumor origin. We identified microRNA biomarkers for the differential diagnosis of MPM and developed a standardized microRNA-based assay. Formalin-fixed, paraffin-embedded samples of 33 MPM and 210 carcinomas were used for assay development. Using microarrays, we identified microRNAs differentially expressed between MPM and various carcinomas. Hsa-miR-193-3p was overexpressed in MPM, while hsa-miR-200c and hsa-miR-192 were overexpressed in peripheral lung adenocarcinoma and carcinomas that frequently metastasize to lung pleura. We developed a standardized diagnostic assay based on the expression of these microRNAs. The assay reached a sensitivity of 100% and a specificity of 94% in a blinded validation set of 68 samples from the lung and pleura. This diagnostic assay can provide a useful tool in the differential diagnosis of MPM from other malignancies in the pleura.

In plain English

This study, funded by Rosetta Genomics, developed and tested a test to tell malignant pleural mesothelioma (MPM) apart from other cancers in the lung and pleura, including lung adenocarcinoma and metastatic cancers. It did not study asbestos exposure. It used stored tumor samples from Israel and the US. First, 7 MPM and 97 carcinoma samples were compared; 11 microRNAs (small gene-regulating molecules) differed significantly. Three were chosen: hsa-miR-200c, hsa-miR-192 and hsa-miR-193a-3p. In a training set, using preliminary cutoffs, 31 of 32 MPM samples (sensitivity 97%, 95% confidence interval 84% to 100%) and 108 of 113 non-MPM samples (specificity 96%, confidence interval 90% to 99%) were placed correctly; final thresholds were then set on 39 of them. In a blinded validation set, 5 of 68 samples failed quality checks. Of the other 63, the test correctly identified all 14 MPM samples (sensitivity 100%) and 46 of 49 carcinomas (specificity 94%), including all 16 lung adenocarcinomas. The authors concluded that the three-microRNA test could accurately diagnose MPM. Most authors worked for, or held equity in, the company developing the test.

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: Diagnostic test development and validation study on stored (formalin-fixed, paraffin-embedded) tumor tissue samples, in three phases: discovery, training and blinded validation
• Who was studied: Tumor tissue samples from resection specimens obtained from medical centers in Israel and two US sources. Across all phases there were 47 mesothelioma samples and 259 carcinoma samples (Table 1). The blinded validation set was 68 samples of tumors from the lung or pleura, of which 63 were analyzed: 14 MPM and 49 various carcinomas. Dates are not given.
• Exposure: Asbestos exposure was not studied. The study measured the levels of three microRNAs (hsa-miR-200c, hsa-miR-193a-3p, hsa-miR-192) in tumor tissue.
• Main results:
  • Discovery phase (7 MPM samples versus 97 carcinoma samples): 111 microRNAs passed the background criterion. Of these, 11 showed significant differences in expression between the two groups.
  • Three microRNAs were chosen as markers. Hsa-miR-200c was high in non-RCC carcinomas and low in MPM. Hsa-miR-192 was high in renal cell carcinoma (RCC) and low in MPM. Hsa-miR-193a-3p was high in MPM.
  • Full training set, using preliminary cutoffs: 31 of 32 MPM samples fell above both cutoffs (sensitivity 97%; 95% confidence interval 84% to 100%).
  • Full training set, using preliminary cutoffs: 108 of 113 non-MPM samples fell below at least one cutoff (specificity 96%; confidence interval 90% to 99%).
  • The final decision thresholds were then set using a subset of the training set: 16 MPM samples and 23 carcinoma samples.
  • Validation: 5 of 68 samples (7%) failed quality assurance criteria and were excluded.
  • Validation: the test correctly classified 60 of 63 blinded samples (95%), including all 14 MPM samples (sensitivity 100%) and 46 of 49 carcinomas (specificity 94%).
  • Validation: 52 of 63 samples (83%) were classified outside the 'near cutoff' region, and all of these were correct.
  • Validation: all 16 lung adenocarcinoma samples were correctly identified as non-mesothelioma, outside the near cutoff region.
  • Telling RCC apart from MPM was difficult because no single microRNA clearly separated the two.
• The authors' conclusion: The authors concluded that their test, using only three microRNAs, can accurately diagnose MPM and distinguish it from lung adenocarcinoma and other malignancies involving the lung and pleura.
• Limitations the authors state:
  • The authors noted that the test's performance still needed to be characterized on poorly differentiated tumors and on other sample types, such as small biopsies and pleural effusions.
  • The authors disclosed that most of them are or were employees of, and/or hold equity in, Rosetta Genomics. The company supported the study, develops microRNA-based diagnostic products and may stand to gain from publication.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleura, Confounding, Lung Adenocarcinoma, Biomarker, Differential Diagnosis, Carcinoma, Metastasis.

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