Long non coding RNAs (lncRNAs) are dysregulated in Malignant Pleural Mesothelioma (MPM)

Our plain-English summary of Long non coding RNAs (lncRNAs) are dysregulated in Malignant Pleural Mesothelioma (MPM), by C.M. Wright, M.B. Kirschner, Y.Y. Cheng, et al (PloS One, 2013).

The study

• Authors: C.M. Wright, M.B. Kirschner, Y.Y. Cheng, K.J. O'Byrne, S.G. Gray, K. Schelch, M.A. Hoda, S. Klebe, B. McCaughan, N. van Zandwijk, G. Reid
• Journal: PloS One
• Published: 2013;8(8):e70940
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer that is often diagnosed at an advanced stage and is characterized by a long latency period (20-40 years between initial exposure and diagnosis) and prior exposure to asbestos. Currently accurate diagnosis of MPM is difficult due to the lack of sensitive biomarkers and despite minor improvements in treatment, median survival rates do not exceed 12 months. Accumulating evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) play an important functional role in cancer biology. LncRNAs are a class of recently discovered non-protein coding RNAs >200 nucleotides in length with a role in regulating transcription. Here we used NCode long noncoding microarrays to identify differentially expressed lncRNAs potentially involved in MPM pathogenesis. High priority candidate lncRNAs were selected on the basis of statistical (P<0.05) and biological significance (>3-fold difference). Expression levels of 9 candidate lncRNAs were technically validated using RT-qPCR, and biologically validated in three independent test sets: (1) 57 archived MPM tissues obtained from extrapleural pneumonectomy patients, (2) 15 cryopreserved MPM and 3 benign pleura, and (3) an extended panel of 10 MPM cell lines. RT-qPCR analysis demonstrated consistent up-regulation of these lncRNAs in independent datasets. ROC curve analysis showed that two candidates were able to separate benign pleura and MPM with high sensitivity and specificity, and were associated with nodal metastases and survival following induction chemotherapy. These results suggest that lncRNAs have potential to serve as biomarkers in MPM.

In plain English

This laboratory study did not look at asbestos exposure. The authors used microarrays to compare long non-coding RNAs (lncRNAs), RNA that does not make protein, in four malignant pleural mesothelioma (MPM) cell lines and one normal mesothelial line. Of 44 differing candidates, 11 proved to be mRNA, leaving 33; a second test (RT-qPCR) confirmed nine. Frozen tumour from 14 MPM patients was compared with 3 benign pleura samples. Two lncRNAs were significantly higher in the MPM tissue: BX648695 (2.95-fold, P = 0.028) and NR_003584 (5-fold, P = 0.038). Each separated the two with 100% specificity and sensitivities of 78.6% and 78.5%. A panel of six lncRNAs correctly classified 76% of these samples. In 57 archived tumours from extrapleural pneumonectomy patients, higher AK054908 was associated with N1 lymph node spread (P = 0.005). Survival did not differ significantly overall between high and low expression groups. Among patients without induction chemotherapy, however, higher EF177379 was associated with longer median survival (19.7 versus 9.5 months, P = 0.019). The authors concluded that lncRNAs have potential as MPM biomarkers but need testing in a larger cohort.

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: microarray profiling of cell lines, with RT-qPCR validation in further cell lines and in patient tumour tissue
• Who was studied: The study used several groups: 4 MPM cell lines plus the normal mesothelial line MeT-5A (microarray); an extended panel of 10 MPM cell lines; fresh-frozen tissue from 14 MPM patients and 3 benign pleura samples (one with pleural plaques) from the Leicestershire Mesothelioma Tissue Bank; and 57 archived (FFPE) MPM tissues from extrapleural pneumonectomy patients in Sydney, collected 1994 to 2009
• Exposure: No asbestos exposure was studied. The study measured lncRNA expression levels in MPM compared with normal or benign mesothelial cells and tissue.
• Main results:
  • Microarrays identified 44 lncRNAs highly differentially expressed in MPM cell lines compared with MeT-5A. Eleven were later reclassified as mRNA transcripts, leaving 33 candidate lncRNAs.
  • Of 22 lncRNAs tested by RT-qPCR in the cell lines, 8 were not detected, 5 did not validate in the same direction, and 9 were validated.
  • In the 14 MPM versus 3 benign pleura tissues, BX648695 (2.95-fold, P = 0.028) and NR_003584 (5-fold, P = 0.038) were significantly higher in MPM. Four other lncRNAs differed but did not reach significance.
  • BX648695 separated benign pleura from MPM with accuracy 93%, sensitivity 78.6% and specificity 100% (AUC 0.93, 95% confidence interval 0.793 to 1.064, as printed, P = 0.023).
  • NR_003584 separated benign pleura from MPM with accuracy 90.5%, sensitivity 78.5% and specificity 100% (AUC 0.905, 95% confidence interval 0.752 to 1.057, P = 0.033).
  • In the 3 benign pleura and 14 MPM tissues, the six-lncRNA panel's best models correctly classified 76% of samples. Sensitivity was 71.4%, specificity 100%, PPV 100% and NPV 43% (P = 0.179 and P = 0.169).
  • In the 57 archived FFPE tumours, higher AK054908 expression was significantly associated with N1 (ipsilateral bronchopulmonary/hilar) lymph node metastasis (P = 0.005).
  • In the FFPE tumours, AK130275 levels were significantly lower in patients who received induction chemotherapy (0.763 versus 1.578 with no chemotherapy, P = 0.002). The same was true of AF268386 (0.956 versus 1.685, P = 0.033).
  • Splitting the FFPE cases into high and low expression at the median showed no significant survival differences.
  • For EF177379 (NEAT1), there was a non-significant trend toward longer survival with higher expression: 19.3 months versus 13.3 months for low expression (P = 0.065).
  • Among patients who did not receive induction chemotherapy, higher EF177379 levels were associated with better overall survival (log-rank P = 0.019).
  • In that subgroup, median survival was 19.7 months with high EF177379 expression versus 9.5 months with low expression.
  • No significant relationship was observed between lncRNA expression and histological subtype.
• The authors' conclusion: The authors concluded that lncRNAs have potential to serve as biomarkers in MPM.
• Limitations the authors state:
  • The tissue test cohort was small, so lncRNAs that did not reach significance cannot be excluded as markers.
  • The lncRNA signature needs to be assessed in a larger cohort.
  • MPM cell lines can show changes caused by growing in the laboratory.
  • It was not tested whether these lncRNAs can tell malignant mesothelioma apart from lung cancer or from benign asbestos-related diseases.

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, Latency, Biomarker, Median Survival, Extrapleural Pneumonectomy (EPP), Pleura, Chemotherapy.

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• Clinical significance of serum DRAM1 mRNA, ARSA mRNA, hsa-miR-2053 and lncRNA-RP1-86D1.3 axis expression in malignant pleural mesothelioma — M. Matboli, A.E. Shafei, et al. (2019)
• The lncRNAs Gas5, MALAT1 and SNHG8 as diagnostic biomarkers for epithelial malignant pleural mesothelioma in Egyptian patients — D.M. Elkahwagy, C.J. Kiriacos, et al. (2024)
• Circulating microRNAs found dysregulated in ex-exposed asbestos workers and pleural mesothelioma patients as potential new biomarkers — I. Bononi, M. Comar, et al. (2016)
• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)

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