Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

Our plain-English summary of Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma, by A. Truini, S. Coco, E. Nadal, et al (Oncotarget, 2017).

The study

• Authors: A. Truini, S. Coco, E. Nadal, C. Genova, M. Mora, M.G. Dal Bello, I. Vanni, A. Alama, E. Rijavec, F. Biello, G. Barletta, D.F. Merlo, A. Valentino, P. Ferro, G.L. Ravetti, S. Stigliani, A. Vigani, F. Fedeli, D.G. Beer, S. Roncella, F. Grossi
• Journal: Oncotarget
• Published: 2017;8(40):68627-68640
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18-8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

In plain English

This laboratory study sought tumor markers of survival in malignant pleural mesothelioma patients who did not have the tumor surgically removed. The authors measured microRNAs, small regulatory molecules, in biopsies from 27 patients in Genoa, Italy. They compared patients who died within 12 months of diagnosis with those who lived beyond 36 months. Of 35 microRNAs linked to survival, 12 were also linked in public data from 72 patients. The top three, miR-99a, let-7c and miR-125b, sit together on chromosome 21. A risk score built from them was tested in 30 further patients from La Spezia, Italy. There, high-risk patients had a median survival of 7.6 months (95% CI 4.4 to 10.9); the low-risk median was not reached. After adjusting for age and tumor subtype, a high-risk score was associated with shorter survival (hazard ratio 3.14, 95% CI 1.18 to 8.34). Asbestos exposure was reported in 22 of 27 and 20 of 30 patients, unknown in the rest. The authors concluded low levels of these microRNAs could have prognostic significance. They named the small validation set as a limitation.

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: Prognostic biomarker study of archived tumor biopsies. microRNA microarray profiling in a training set was followed by checking against public TCGA sequencing data and by validation with quantitative PCR in an independent set of patients.
• Who was studied: Patients with malignant pleural mesothelioma who did not undergo surgery. The training set was 27 patients diagnosed at the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy (26 analyzed after one sample failed quality control). The validation set was 30 patients at San Andrea Hospital, La Spezia, Italy. Public TCGA data on 72 patients were also used. Short survivors died within 12 months (15 training, 16 validation); long survivors lived more than 36 months (12 training, 14 validation). Patients who had surgery or were over 80 at diagnosis were excluded. Four nonmalignant pleural samples from lung cancer lobectomies served as controls. No study dates are given.
• Exposure: The factor studied was tumor microRNA expression, not asbestos. Asbestos exposure was recorded only as a patient characteristic: yes for 22 of 27 training-set patients (81%) and 20 of 30 validation-set patients (67%), unknown for the rest. It did not differ significantly between the sets. No fiber types, jobs or doses are given.
• Main results:
  • In the training set, 91 microRNAs differed in level between 26 mesothelioma tumors and 3 nonmalignant pleura samples (p less than 0.05).
  • Of the 35 microRNAs linked to survival in the training set, 12 remained statistically associated with overall survival in the TCGA data from 72 patients.
  • In the training set, patients with low expression of miR-99a, let-7c and miR-125b had median overall survival of 2.9, 2.9 and 3.4 months respectively. Median survival was not reached for patients with high expression.
  • In the TCGA dataset, patients with low expression of the three microRNAs had median overall survival of 10.9 months for each marker. Patients with high expression had medians of 19.7, 19.7 and 24.1 months.
  • In the validation set of 30 patients, those with a high risk score had median overall survival of 7.6 months (95% CI 4.4 to 10.9). Median survival was not reached for low-risk patients (log-rank p=0.042). Survival at 24 months was 27.7% for high-risk and 66.7% for low-risk patients.
  • In the validation set, after adjustment for age and histological subtype, a high risk score was independently associated with shorter overall survival (HR 3.14; 95% CI 1.18 to 8.34; p=0.022).
  • Copy-number testing of the chromosome 21 region holding the three microRNAs was done in 44 of 57 patients. It found no copy-number changes at the cluster.
• The authors' conclusion: The authors concluded that low expression of the chromosome 21q21.1 microRNA cluster could have prognostic significance in patients who did not have surgery. They described it as, to their knowledge, the first prognostic signature for such patients.
• Limitations the authors state:
  • The validation set was relatively small, because samples from long-surviving patients who did not have surgery are hard to collect.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Overall Survival.

Related studies

• Prognostic and Therapeutic Implications of MicroRNA in Malignant Pleural Mesothelioma — A. Truini, S. Coco, et al. (2016)
• Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report — I. Vanni, S. Coco, et al. (2016)
• Two Different Serum MiRNA Signatures Correlate with the Clinical Outcome and Histological Subtype in Pleural Malignant Mesothelioma Patients — M. Lamberti, R. Capasso, et al. (2015)
• Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome — B.C. Christensen, E.A. Houseman, et al. (2009)
• CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome — E. Ortolan, A. Giacomino, et al. (2014)
• YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations — R. Cunningham, S. Jia, et al. (2023)

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