Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma

Our plain-English summary of Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma, by Z. Lu, W. Zhang, K. Huang, et al (Diagnostics, 2022).

The study

• Authors: Z. Lu, W. Zhang, K. Huang, M. Zhu, X. Gu, D. Wei, M. Shi, Y. Chen, H. Wang
• Journal: Diagnostics
• Published: 2022;12(9)
• Type of article: Review
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51-0.78) and 0.91 (95% CI, 0.82-0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85-0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.

In plain English

This systematic review and meta-analysis pooled studies of three markers proposed for diagnosing malignant pleural mesothelioma (MPM): mesothelin (MSLN), soluble mesothelin-related peptides (SMRP) and Fibulin-3. It included 31 studies (2003 to 2018) with 1950 MPM patients and 6800 non-MPM patients. Pooled sensitivity was 0.66 (95% CI 0.51 to 0.78) for MSLN and 0.68 (0.63 to 0.73) for SMRP. Pooled specificity was 0.91 (0.82 to 0.96) and 0.86 (0.82 to 0.90). For Fibulin-3 the abstract gives sensitivity 0.90 (0.74 to 0.97) and specificity 0.91 (0.84 to 0.95), but the results section prints intervals that exclude these estimates. Fibulin-3 had the highest area under the curve, 0.96 (0.93 to 0.97). The authors also analysed gene data from 86 tumour tissues in The Cancer Genome Atlas. The results section reports that higher MSLN gene expression went with longer survival (p = 0.011), while the abstract states the reverse. EFEMP1, the gene for Fibulin-3, showed no statistically significant link with survival. The authors concluded Fibulin-3 could be one member of a combined diagnostic panel. They noted that the studies differed in size, clinical typing and test thresholds.

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: Systematic review and meta-analysis of diagnostic accuracy studies, plus a bioinformatic survival analysis of gene-expression data from The Cancer Genome Atlas (TCGA)
• Who was studied: 31 published studies (2003 to 2018), found in PubMed, Embase and Cochrane Library up to March 2021, totalling 1950 MPM patients and 6800 non-MPM patients
• Exposure: Diagnostic markers MSLN, SMRP and Fibulin-3 (meta-analysis). MSLN and EFEMP1 (Fibulin-3) gene expression in 86 TCGA tumor tissues (survival analysis). Asbestos exposure was not analysed.
• Main results:
  • MSLN: pooled sensitivity 0.66 (95% CI 0.51 to 0.78) and pooled specificity 0.91 (95% CI 0.82 to 0.96)
  • SMRP: pooled sensitivity 0.68 (95% CI 0.63 to 0.73) and pooled specificity 0.86 (95% CI 0.82 to 0.90)
  • Fibulin-3: pooled sensitivity 0.90 and pooled specificity 0.91. The article's abstract gives 95% CIs of 0.74 to 0.97 and 0.84 to 0.95. The results section prints 0.63 to 0.73 and 0.82 to 0.90, which do not contain the point estimates.
  • All studies pooled (MSLN + SMRP + Fibulin-3): pooled sensitivity 0.74 (95% CI 0.66 to 0.80) and pooled specificity 0.89 (95% CI 0.85 to 0.91)
  • Area under the SROC curve: 0.85 (95% CI 0.82 to 0.88) for MSLN, 0.83 (95% CI 0.80 to 0.86) for SMRP, 0.96 (95% CI 0.93 to 0.97) for Fibulin-3, and 0.90 (95% CI 0.87 to 0.92) for the three combined
  • In the TCGA mesothelioma data, survival time differed significantly between high and low MSLN gene expression groups (log-rank p = 0.011)
  • According to the results section, higher MSLN gene expression was associated with longer survival in MPM patients. The article's own abstract states that low expression was related to longer survival.
  • Cox regression indicated that MSLN could be an independent prognostic indicator (HR below 1, p less than 0.05)
  • For the EFEMP1 gene (which encodes Fibulin-3), all subgroup survival analyses showed differences that were not statistically significant
  • Deeks' funnel plot test for publication bias gave p = 0.83; the authors interpreted this as no publication bias
• The authors' conclusion: The authors concluded that Fibulin-3, compared with the other markers, can be used as one member of a combined biomarker diagnostic panel, and that higher MSLN gene expression was linked to longer survival and better prognosis in MPM patients.
• Limitations the authors state:
  • The included studies differed significantly in number of participants, clinical typing and diagnostic thresholds
  • Most studies left open whether samples stayed stable when sent to the laboratory for testing
  • The gene-expression analysis was limited by small sample size

Topics

Medical terms in this study, explained in our Lexicon: Systematic Review, Meta-Analysis, Biomarker, Prognosis, Pleural Mesothelioma, Fibulin-3, Mesothelin, Soluble Mesothelin-Related Peptides (SMRP).

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