MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma

Our plain-English summary of MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma, by M.B. Kirschner, Y.Y. Cheng, N.J. Armstrong, et al (Molecular Oncology, 2015).

The study

• Authors: M.B. Kirschner, Y.Y. Cheng, N.J. Armstrong, R.C. Lin, S.C. Kao, A. Linton, S. Klebe, B.C. McCaughan, N. van Zandwijk, G. Reid
• Journal: Molecular Oncology
• Published: 2015;9(3):715-26
• Cited by: 59 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Prognosis of malignant pleural mesothelioma (MPM) is poor, and predicting the outcomes of treatment is difficult. Here we investigate the potential of microRNA expression to estimate prognosis of MPM patients.

Methods: Candidate microRNAs from microarray profiling of tumor samples from 8 long (median: 53.7 months) and 8 short (median: 6.4 months) survivors following extrapleural pneumonectomy (EPP) were validated by RT-qPCR in 48 additional EPP samples. Kaplan-Meier log ranking was used to further explore the association between microRNA expression and overall survival (OS). Binary logistic regression was used to construct a microRNA signature (miR-Score) that was able to predict an OS of ≥20 months. Performance of the miR-Score was evaluated by receiver operating characteristic (ROC) curve analysis and validated in a series of 43 tumor samples from patients who underwent palliative surgery [pleurectomy/decortication (P/D)].

Results: The miR-Score, using expression data of six microRNAs (miR-21-5p, -23a-3p, -30e-5p, -221-3p, -222-3p, and -31-5p), enabled prediction of long survival with an accuracy of 92.3% for EPP and 71.9% for palliative P/D. Hazard ratios for score-negative patients were 4.12 (95% CI: 2.03-8.37) for EPP and 1.93 (95% CI: 1.01-3.69) for P/D. Importantly, adding the miR-Score to a set of clinical selection criteria (histology, age, gender) increased predictive accuracy in the independent validation set from 76.3% for clinical factors only to 87.3%.

Conclusions: This study has identified a novel 6-microRNA signature (miR-Score) that can accurately predict prognosis of MPM patients.

Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

In plain English

This retrospective laboratory study from Sydney, Australia, asked whether levels of small RNA molecules called microRNAs in tumor tissue could predict survival in malignant pleural mesothelioma. It did not examine asbestos exposure. The authors compared stored tumors from 8 long and 8 short survivors of radical surgery (extrapleural pneumonectomy, EPP). They then tested candidate microRNAs in 48 more EPP patients and built a six-microRNA "miR-Score" to predict survival of at least 20 months. In these EPP patients the authors reported a predictive accuracy of 92.3%. Score-positive patients had an odds ratio of 19.44 (95% CI 4.20 to 90.03) for surviving 20 months. In 43 patients who had palliative pleurectomy/decortication, accuracy was 71.9%, and survival was 15.4 months for score-positive patients versus 6.5 months for score-negative patients. In that group, adding the score to age, gender and tumor type raised the area under the curve, a measure of accuracy, from 0.763 to 0.873. This increase was not statistically significant. The authors concluded that the score appears to have prognostic value but needs validation in a prospective study and in pre-treatment samples.

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: Retrospective study of archival tumor samples: microRNA profiling, building a prognostic microRNA signature in one surgical group, and testing it in a second surgical group
• Who was studied: Patients with malignant pleural mesothelioma treated in Sydney, Australia. The first group was 64 patients who had extrapleural pneumonectomy (EPP) at Royal Prince Alfred or Strathfield Private Hospitals between October 1994 and November 2009: 16 formed a discovery set (8 long and 8 short survivors) and 48 a training set. The second group was 43 of 75 consecutive patients who had palliative pleurectomy/decortication (P/D) at Royal Prince Alfred Hospital between October 1991 and October 2006 and had usable RNA; this was the validation set.
• Exposure: Asbestos exposure was not studied. The factor examined was microRNA levels in tumor tissue. The final miR-Score combined six microRNAs: miR-21-5p, -23a-3p, -30e-5p, -221-3p, -222-3p and -31-5p.
• Main results:
  • In the discovery set (8 long and 8 short EPP survivors), microarray profiling found 16 microRNAs that differed at least 2-fold between the groups. Twelve of these were at lower levels in long survivors.
  • In the EPP training set (48 patients), lower expression of 9 microRNAs was significantly associated with up to 14.9 months longer overall survival. After adjusting for histological subtype, gender and age, miR-21-5p, miR-19b-3p, miR-625-3p and miR-106b-5p remained significant.
  • In the EPP training set, the six-microRNA miR-Score had an area under the curve (AUC) of 0.867 (95% CI 0.76 to 0.96), and an average AUC of 0.922 after 500 bootstrap re-samples. At a cut-off score of 0.44, sensitivity was 82.4% and specificity 80.6%.
  • In the EPP training set, score-positive patients had an odds ratio of 19.44 (95% CI 4.20 to 90.03, P = 0.0001) for survival of 20 months. The survival difference between score-positive and score-negative groups was 22.9 months, and the hazard ratio for score-negative patients was 4.12 (P = 0.00009).
  • In the EPP training set, adding the miR-Score to clinical factors raised the AUC from 0.601 (95% CI 0.437 to 0.764) to 0.844 (95% CI 0.707 to 0.982).
  • In the P/D validation set (43 patients), score-positive patients had an odds ratio of 9.72 (95% CI 1.70 to 55.75, P = 0.011) for good prognosis. The score predicted good prognosis with an accuracy of 71.9% (AUC 0.719, 95% CI 0.535 to 0.902).
  • In the P/D validation set, score-positivity was associated with a survival benefit of 8.9 months: 15.4 months versus 6.5 months (P = 0.044).
  • In the P/D validation set, adding the miR-Score to clinical factors raised the AUC from 0.763 to 0.873. This increase did not reach statistical significance.
• The authors' conclusion: The authors concluded that the miR-Score appears to have prognostic significance in malignant pleural mesothelioma patients. They stated that it still requires additional validation in a prospective study and in pre-treatment samples.
• Limitations the authors state:
  • All prognostic calculations were done in retrospect from relatively small sample numbers, and sufficient RNA could not be isolated from all samples.
  • In the EPP cohort, pathological stage was distributed differently between patients with and without usable RNA. The authors said this did not affect the analysis because stage was excluded.
  • Both cohorts came from a single institution, and most operations (all EPPs and 71% of P/Ds) were done by a single surgeon. The authors said this could be a confounding factor.
  • There was no validation cohort that received the same treatment (EPP) as the training cohort.
  • Each patient's score was calculated relative to all patients in the series, which the authors described as a technical challenge for using it on individual patients.

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: Pleural Mesothelioma, Prognosis, Extrapleural Pneumonectomy (EPP), Overall Survival, Palliative Care, Pleurectomy/Decortication (P/D), Hazard Ratio, Histology.

Related studies

• miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma — M. Williams, M.B. Kirschner, et al. (2015)
• MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications — S. Busacca, S. Germano, et al. (2010)
• Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2012)
• ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma — Y.Y. Cheng, M.B. Kirschner, et al. (2013)
• A Significant Metabolic and Radiological Response after a Novel Targeted MicroRNA-based Treatment Approach in Malignant Pleural Mesothelioma — S.C. Kao, M. Fulham, et al. (2015)
• Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma — S.C. Kao, Y.Y. Cheng, et al. (2017)

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