Prognostic value of midkine, syndecan-1, hyaluronan synthase-2, sestrin-1, laminin subunit alpha-4 and fibulin-3 for malignant pleural mesothelioma

Our plain-English summary of Prognostic value of midkine, syndecan-1, hyaluronan synthase-2, sestrin-1, laminin subunit alpha-4 and fibulin-3 for malignant pleural mesothelioma, by H. Akgun, S. Metintas, G. Ak, et al (Archives of Medical Science, 2023).

The study

• Authors: H. Akgun, S. Metintas, G. Ak, S. Demirkol Canlı, M. Isbilen, A.O. Gure, M. Metintas
• Journal: Archives of Medical Science
• Published: 2023;19(2):355-364
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: The prognosis of malignant pleural mesothelioma (MPM) is poor, with a limited survival time. In this study, we aimed to examine expression levels of genes selected from relevant literature and to utilize in silico methods to determine genes whose expression could reflect the prognosis of patients with MPM by ex-vivo validation experiments.

Material And Methods: The study group consisted of 54 MPM patients treated with chemotherapy. Expression of 6 genes - midkine (MDK), syndecan-1 (SDC1), hyaluronan synthase-2 (HAS2), sestrin-1 (SESN1), laminin subunit alpha-4 (LAMA4), and fibulin-3 (FBLN3) - was examined by qPCR in tumor tissues. Sestrin-1 and LAMA4 were identified using an in house R-based script: Unsupervised Survival Analysis Tool. Midkine, SDC1, HAS2, and FBLN3 were selected from current literature. We used two housekeeping genes, i.e. glucose-6-phosphate dehydrogenase and TATA-box binding protein, as controls.

Results: Of the patients, 43 (79.6%) had epithelioid mesothelioma. The median survival for all patients was 10 (±1.2 SE) months (95% CI: 7.7-12.3). In multivariate analyses, MDK (p = 0.007), HAS2 (p = 0.008) and SESN1 (p = 0.014) expression levels were related to survival time in the whole group. In epithelioid type MPM patients, MDK (p = 0.014), FBLN3 (p = 0.029), HAS2 (p = 0.014) and SESN1 (p = 0.045) expression was related to survival time in multivariate analyses.

Conclusions: High HAS2 and SESN1 expressions and low MDK are potential biomarkers of good prognosis in MPM. High HAS2 and SESN1 expression and low MDK and FBLN3 can also be utilized as biomarkers of good prognosis for epithelioid MPM. Those results should be further investigated in sera, plasma, and pleural effusions.

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In plain English

This study, done at Eskisehir Osmangazi University in Turkey between 2015 and 2017, looked at 54 patients with malignant pleural mesothelioma treated with chemotherapy. All had a history of asbestos exposure: 92.6% environmental and 7.4% occupational. The article does not name fiber types. The researchers measured how active six genes were in tumor tissue and compared this with survival. Median survival was 10.0 months (95% confidence interval 7.7 to 12.3). After accounting for tumor type, stage and performance score, high midkine (MDK) activity was linked to shorter survival (hazard ratio 3.89, 95% CI 1.46 to 10.40). So were low HAS2 (2.77, 1.30 to 5.92) and low sestrin-1 (4.0, 1.33 to 12.01). Syndecan-1 fell short of statistical significance in that analysis. Fibulin-3 and LAMA4 showed no statistically significant link with survival after adjustment, although high fibulin-3 was linked to worse survival before adjustment. Among the 43 patients with epithelioid tumors, high fibulin-3 was linked to shorter survival (hazard ratio 5.93, 95% CI 1.20 to 29.22). The authors concluded that MDK, HAS2 and SESN1 were potentially useful biomarkers. They named the small number of patients 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: Single-center study of patients with malignant pleural mesothelioma, measuring gene expression in tumor tissue (by qPCR) and relating it to survival; carried out at Eskisehir Osmangazi University Lung and Pleural Cancers Research and Clinical Center, Turkey, March 2015 to March 2017
• Who was studied: 54 patients with malignant pleural mesothelioma (MPM) treated with chemotherapy; 43 (79.6%) had epithelioid mesothelioma
• Exposure: All patients had a history of asbestos exposure: 92.6% environmental, 7.4% occupational; fiber types and doses are not reported. The factor studied was tumor-tissue expression of six genes: midkine (MDK), syndecan-1 (SDC1), hyaluronan synthase-2 (HAS2), sestrin-1 (SESN1), laminin subunit alpha-4 (LAMA4) and fibulin-3 (FBLN3)
• Main results:
  • Of the 54 patients, 43 (79.6%) had epithelioid mesothelioma
  • Median survival for all 54 patients was 10.0 months (standard error 1.2; 95% CI 7.7 to 12.3)
  • Whole group, multivariate analysis: high MDK expression compared with low was associated with shorter survival, hazard ratio 3.89 (95% CI 1.46 to 10.40), p = 0.007
  • Whole group, multivariate analysis: low HAS2 expression compared with high was associated with shorter survival, hazard ratio 2.77 (95% CI 1.30 to 5.92), p = 0.008
  • Whole group, multivariate analysis: low SESN1 expression compared with high was associated with shorter survival, hazard ratio 4.0 (95% CI 1.33 to 12.01), p = 0.014
  • Whole group: low SDC1 expression was associated with worse survival after adjustment for stage and Karnofsky Performance Score. In the multivariate analysis this did not reach statistical significance: hazard ratio 2.77 (95% CI 0.99 to 7.74), p = 0.053
  • Whole group, before adjustment (Kaplan-Meier analysis): prognosis was significantly worse in patients whose tumors overexpressed MDK (2.04 or more) and FBLN3 (1.04 or more)
  • Whole group, after adjustment for stage and Karnofsky Performance Score: the associations of FBLN3 (p = 0.657) and LAMA4 (p = 0.472) expression with prognosis were not statistically significant
  • Epithelioid subgroup, multivariate analysis: MDK (p = 0.014), FBLN3 (p = 0.029), HAS2 (p = 0.014) and SESN1 (p = 0.045) expression were independently associated with survival
  • Epithelioid subgroup, multivariate analysis: high FBLN3 expression compared with low had a hazard ratio of 5.93 (95% CI 1.20 to 29.22)
  • Epithelioid subgroup, multivariate analysis: high MDK expression compared with low had a hazard ratio of 4.47 (95% CI 1.35 to 14.78)
• The authors' conclusion: The authors concluded that MDK, HAS2 and SESN1 were potentially useful biomarkers in MPM. In their view, high MDK was associated with poor prognosis and high HAS2 and SESN1 with better prognosis. In epithelioid MPM, high MDK and FBLN3 were associated with poor prognosis. They said the results should be confirmed in a larger group of patients
• Limitations the authors state:
  • The small size of the study population, which the authors said did not allow them to assess and discuss cellular subtypes

Topics

Medical terms in this study, explained in our Lexicon: Fibulin-3, Pleural Mesothelioma, Prognosis, Chemotherapy, Epithelioid, Mesothelioma, Median Overall Survival, Biomarker.

Related studies

• Midkine is a potential novel marker for malignant mesothelioma with different prognostic and diagnostic values from mesothelin — G. Ak, Y. Tada, et al. (2017)
• Diagnostic and prognostic value of soluble syndecan-1 in pleural malignancies — F. Mundt, G. Heidari-Hamedani, et al. (2014)
• Hyaluronan synthase 1: a mysterious enzyme with unexpected functions — H. Siiskonen, S. Oikari, et al. (2015)
• Non-SMC condensin I complex subunit D2 (NCAPD2) reveals its prognostic and immunologic features in human cancers — X. Dong, T. Liu, et al. (2023)
• Diagnostic value of fibulin-3 for malignant pleural mesothelioma: A systematic review and meta-analysis — R. Ren, P. Yin, et al. (2016)
• The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy — N.I. Wahba, O. Khorshid, et al. (2023)

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