Sensitive Blood-Based Detection of Asbestos-Associated Diseases Using Cysteine-Rich Angiogenic Inducer 61 as Circulating Protein Biomarker

Our plain-English summary of Sensitive Blood-Based Detection of Asbestos-Associated Diseases Using Cysteine-Rich Angiogenic Inducer 61 as Circulating Protein Biomarker, by K. Bartkowiak, S. Casjens, A. Andreas, et al (Clinical Chemistry, 2021).

The study

• Authors: K. Bartkowiak, S. Casjens, A. Andreas, L. Ačkar, S.A. Joosse, I. Raiko, T. Brüning, M. Geffken, S. Peine, G. Johnen, D.G. Weber, K. Pantel
• Journal: Clinical Chemistry
• Published: 2021;67(2):363-373
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Detection of asbestos-associated diseases like asbestosis or mesothelioma is still challenging. We sought to improve the diagnosis of benign asbestos-associated disease (BAAD) by detection of the protein cysteine-rich angiogenic inducer 61 (Cyr61) in human plasma.

Methods: Plasma Cyr61 was quantified using an enzyme-linked immunosorbent assay. Plasma samples from males diagnosed with BAAD, but without a malignant disease (n = 101), and malignant mesothelioma (n = 21; 15 males, 6 females), as well as nonasbestos-exposed healthy control participants (n = 150; 58 males, 92 females) were analyzed. Clinical sensitivity and specificity of Cyr61 were determined by receiver operating characteristic analysis.

Results: The median plasma Cyr61 concentration for healthy control participants was 0.27 ng/mL. Cytoplasmic Cyr61 in peripheral blood mononuclear cells from healthy control participants was evenly distributed, as detected by immunofluorescent staining. The increase in plasma Cyr61 concentrations in the BAAD study group was statistically significant compared to the healthy control participants (P < 0.0001). For the detection of BAAD vs male healthy control participants, clinical sensitivity was 88% and clinical specificity 95% with an area under the curve of 0.924 at maximal Youden Index. For a predefined clinical specificity of 100%, the clinical sensitivity was 76%. For male mesothelioma patients vs male healthy control participants, the clinical sensitivity at maximal Youden Index was 95% with a clinical specificity of 100% (area under the curve, 0.997) and for a predefined clinical specificity of 100%, the clinical sensitivity was 93%.

Conclusions: In our study, plasma Cyr61 protein concentrations showed to be a new biomarker for asbestos-associated diseases like BAAD and mesothelioma in men, which deserves further investigation in large-scale cohort studies.

© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: [email protected].

In plain English

This retrospective study tested whether a blood protein, Cyr61, could help detect asbestos-related disease. Plasma Cyr61 was measured in three groups. The first was 101 German men formerly exposed to asbestos with benign asbestos-associated disease (asbestosis, pleural plaques, pleural thickening and/or pleural fibrosis). The second was 21 patients with mesothelioma (15 men, 6 women). The third was 150 healthy people over 50 (58 men, 92 women), described as not exposed to asbestos; no asbestos-exposed people without disease were studied. Median Cyr61 was 14.4 ng/mL in men with benign disease and 0.24 ng/mL in healthy men. Between these male groups, the test detected 88% of men with benign disease and correctly cleared 95% of healthy men. At a stricter cutoff giving no positives among the 58 healthy men, it detected 76% of men with benign disease. Men with mesothelioma also had raised levels (12.5 ng/mL), but women with mesothelioma did not differ significantly from healthy women. Cyr61 levels did not separate benign disease from mesothelioma. The authors concluded Cyr61 might be a new blood biomarker for asbestos-related diseases in men, deserving larger studies.

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 diagnostic study comparing blood plasma levels of the protein Cyr61 between patient groups and healthy controls, with ROC analysis of clinical sensitivity and specificity; also laboratory work on mesothelioma cell lines and blood cells
• Who was studied: Three groups. (1) 101 men with benign asbestos-associated disease (confirmed asbestosis, pleural plaques, pleural thickening and/or pleural fibrosis) from the German MoMar study, recruited at 26 centers across Germany, with samples from June 2010 to July 2016. (2) 21 patients with mesothelioma (15 men, 6 women) from a clinic in Berlin, with samples from February 2009 to November 2016. (3) 150 healthy blood-bank controls over 50 years old (58 men, 92 women), described as not exposed to asbestos, mostly from Hamburg, collected July 2017 to March 2018, plus 10 purchased plasma samples from healthy smokers included in the control group. The study had no group of asbestos-exposed people without disease.
• Exposure: The benign-disease group were German workers formerly exposed to asbestos. The main text does not give fiber types, jobs or doses. The healthy controls are described as not exposed to asbestos. The quantity measured was plasma Cyr61 concentration.
• Main results:
  • Median plasma Cyr61 was 14.4 ng/mL in the 101 men with benign asbestos-associated disease. In the 58 healthy men it was 0.24 ng/mL. The difference was statistically significant (P less than 0.0001).
  • Men with benign asbestos-associated disease vs healthy men: area under the curve 0.924 (95% CI 0.880 to 0.968). At the cutoff that best balanced the two, 0.38 ng/mL, clinical sensitivity was 88% and clinical specificity 95%.
  • At the 0.38 ng/mL cutoff, 88 of 101 men with benign disease tested positive. Among healthy men, 55 of 58 tested negative and 3 of 58 tested falsely positive.
  • At a cutoff of 2.16 ng/mL, none of the 58 healthy men in this study tested positive (100% specificity). At that cutoff, clinical sensitivity was 76% (76 of 101 men with benign disease).
  • All 101 benign-disease patients vs all 150 healthy controls (men and women): area under the curve 0.915 (95% CI 0.869 to 0.960), clinical sensitivity 82%, clinical specificity 97%.
  • Within the benign-disease group, Cyr61 levels did not differ by age group or smoking status. The authors also report no difference by other factors analyzed, such as chronic diseases, medication or asbestos exposure; those analyses are in supplementary tables not included here.
  • In the 15 men with mesothelioma, median Cyr61 was 12.5 ng/mL, compared with 0.24 ng/mL in healthy men (P less than 0.0001).
  • In the 6 women with mesothelioma, median Cyr61 was 0.21 ng/mL. This was not significantly different from the 92 healthy women (0.29 ng/mL).
  • Men with mesothelioma vs healthy men: area under the curve 0.997. The main text reports clinical sensitivity of 100% and specificity of 95% at the best-balanced cutoff; the abstract reports these the other way round. At 100% specificity, sensitivity was 93%. No ROC analysis was done for women because there were only 6.
  • Cyr61 levels did not differ between the men with benign asbestos-associated disease (median 14.4 ng/mL) and the men with mesothelioma (median 12.5 ng/mL). The area under the curve for telling them apart was 0.510.
• The authors' conclusion: The authors concluded that circulating Cyr61 in the blood might be a new biomarker for detecting asbestos-related diseases, such as benign asbestos-associated disease and mesothelioma in men. They said it deserves further investigation in large-scale cohort studies.
• Limitations the authors state:
  • Samples came from different places: healthy controls mainly from Hamburg, mesothelioma cases from Berlin, and benign-disease cases from a nationwide multicenter study. The authors say this might bias the values.
  • Cyr61 could not distinguish benign asbestos-associated disease from mesothelioma.
  • 18% (best-balanced cutoff) or 25% (100%-specificity cutoff) of benign-disease cases were false negatives. The authors say other markers need to be added to raise sensitivity.
  • All benign-disease patients were men, so differences between men and women could not be studied in that group.
  • The mesothelioma group was small.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Biomarker, Mesothelioma, Malignant Mesothelioma.

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