HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients

Our plain-English summary of HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients, by A. Napolitano, D.J. Antoine, L. Pellegrini, et al (Clinical Cancer Research, 2016).

The study

• Authors: A. Napolitano, D.J. Antoine, L. Pellegrini, F. Baumann, I. Pagano, S. Pastorino, C.M. Goparaju, K. Prokrym, C. Canino, H.I. Pass, M. Carbone, H. Yang
• Journal: Clinical Cancer Research
• Published: 2016;22(12):3087-96
• Cited by: 94 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls.

Experimental Design: Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals.

Results: HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non-mesothelioma pleural effusion.

Conclusions: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Clin Cancer Res; 22(12); 3087-96. ©2016 AACR.

©2016 American Association for Cancer Research.

In plain English

This study measured a blood protein, HMGB1, in total and in a chemically modified form called hyper-acetylated HMGB1. The aim was to see whether it could distinguish people with malignant mesothelioma, people occupationally exposed to asbestos, and unexposed people. Blood came from 22 mesothelioma patients, 20 New York City insulation workers with 10 or more years of asbestos exposure, 20 apparently healthy unexposed controls from Liverpool, UK, and patients with benign (13) or non-mesothelioma malignant (25) pleural effusions. Median total HMGB1 was 1.4 ng/ml in controls, 10.2 in exposed workers and 25.0 in mesothelioma patients. Hyper-acetylated HMGB1 was 0.5 ng/ml in controls, 0.4 in exposed workers and 17.4 in mesothelioma patients. At a cut-off of 2.00 ng/ml it separated mesothelioma patients from exposed workers with 100% sensitivity and specificity. Its levels did not differ significantly by tumor stage. Against other pleural effusions, fibulin-3 scored higher than HMGB1, and combining the two scored higher still. The authors concluded that hyper-acetylated HMGB1 was an accurate biomarker. They noted that the sample was small, the groups were unmatched and the workers were heavily exposed, so larger validation was needed.

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 (cell culture) experiments plus a blinded comparison of blood biomarker levels between patient and control groups (diagnostic biomarker study)
• Who was studied: 60 patients in New York City who presented with pleural effusions (22 malignant mesothelioma, 13 benign effusions, 25 malignant non-mesothelioma effusions), recruited 2005 through 2013. Also 20 New York City insulation workers from the Selikoff cohort without pleural effusion or evidence of malignancy, and 20 apparently healthy controls with no known history of asbestos exposure from Liverpool, UK.
• Exposure: Occupational asbestos exposure of 10 or more years in insulation workers; the fiber type is not stated for the human subjects. In the laboratory, human mesothelial cells were exposed to crocidolite asbestos at 5 micrograms per square centimetre.
• Main results:
  • In cell culture, mesothelial cells exposed to crocidolite asbestos released high levels of non-acetylated HMGB1. Mesothelioma cells released hyper-acetylated HMGB1 as well as non-acetylated HMGB1.
  • Total HMGB1 (median, 1st to 3rd quartile) was 10.2 (5.7 to 12.1) ng/ml in asbestos-exposed individuals, significantly higher than in unexposed healthy controls, at 1.4 (0.8 to 2.2) ng/ml; P less than 0.001.
  • Mesothelioma patients had the highest total HMGB1, 25.0 (15.7 to 36.6) ng/ml, compared with either other group (P less than 0.001).
  • Hyper-acetylated HMGB1 was very low in healthy controls, 0.5 (0.3 to 0.7) ng/ml, and in asbestos-exposed individuals, 0.4 (0.3 to 0.6) ng/ml.
  • Mesothelioma patients had significantly higher hyper-acetylated HMGB1, 17.4 (10.3 to 21.9) ng/ml, than either other group (P less than 0.001).
  • Comparing asbestos-exposed individuals with healthy controls, the area under the curve (AUC) was 0.964 (95% CI 0.893 to 1.000) for total HMGB1 and 0.574 (95% CI 0.392 to 0.756) for hyper-acetylated HMGB1.
  • Comparing mesothelioma patients with asbestos-exposed individuals, the AUC of total HMGB1 was 0.830 (95% CI 0.687 to 0.972).
  • Comparing mesothelioma patients with asbestos-exposed individuals, the AUC of hyper-acetylated HMGB1 was 1.000 (95% CI 1.000 to 1.000), with a cut-off of 2.00 ng/ml.
  • There was no significant difference in total or hyper-acetylated HMGB1 between mesothelioma patients at stage I to II and those at stage III to IV.
  • Comparing mesothelioma patients with asbestos-exposed individuals, the AUCs of the other biomarkers were: fibulin-3 0.959 (95% CI 0.905 to 1.000), mesothelin 0.934 (95% CI 0.858 to 1.00) and osteopontin 0.961 (95% CI 0.910 to 1.000).
  • Comparing mesothelioma patients with patients who had pleural effusions from other causes, total HMGB1 (AUC 0.860) and hyper-acetylated HMGB1 (AUC 0.837) performed better than osteopontin and mesothelin.
  • In the same comparison against other pleural effusions, fibulin-3 had an AUC of 0.928 (95% CI 0.868 to 0.989).
  • Combining fibulin-3 with total HMGB1 gave an AUC of 0.987 (0.967 to 1.000), and combining it with hyper-acetylated HMGB1 gave 0.981 (0.956 to 1.000), for distinguishing mesothelioma patients from patients with pleural effusions due to other causes.
• The authors' conclusion: The authors concluded that their results provide the first biomarker of asbestos exposure. They also concluded that hyper-acetylated HMGB1 is an accurate biomarker for distinguishing mesothelioma patients from occupationally exposed individuals and unexposed controls, while stating that the findings need independent validation in a larger cohort.
• Limitations the authors state:
  • The sample size was relatively small, which could lead to over-fitting of the data.
  • Patients and controls were not strictly matched on demographic or epidemiologic factors, so confounding is possible.
  • The exposed workers were heavily exposed insulators, so it is not known whether HMGB1 rises with lower asbestos exposure.
  • Because of the small sample, no reliable multivariate model explaining variation in HMGB1 levels was found.
  • The findings need independent validation in a larger cohort before clinical use.

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: High Mobility Group Box 1 (HMGB1), Biomarker, Asbestos Exposure, Mesothelioma, Malignant Mesothelioma, Pleural Effusion, Fibulin-3, Mesothelin.

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• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• HMGB1 as a Potential Biomarker and Therapeutic Target for Malignant Mesothelioma — Y. Wang, Z. Jiang, et al. (2019)
• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma — J.S. Suarez, F. Novelli, et al. (2023)
• Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma — K. Shiomi, Y. Hagiwara, et al. (2008)

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