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

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2016 Jan 7

PMID 26733616

Citations 60

Authors

Andrea Napolitano

Daniel J Antoine

Laura Pellegrini

Francine Baumann

Ian Pagano

Sandra Pastorino

Chandra M Goparaju

Kirill Prokrym

Claudia Canino

Harvey I Pass

Michele Carbone

Haining Yang

Affiliations

Soon will be listed here.

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.

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References

Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A . Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003; 22(20):5551-60. PMC: 213771. DOI: 10.1093/emboj/cdg516. View

Schneider J, Hoffmann H, Dienemann H, Herth F, Meister M, Muley T . Diagnostic and prognostic value of soluble mesothelin-related proteins in patients with malignant pleural mesothelioma in comparison with benign asbestosis and lung cancer. J Thorac Oncol. 2008; 3(11):1317-24. DOI: 10.1097/JTO.0b013e318187491c. View

Testa J, Cheung M, Pei J, Below J, Tan Y, Sementino E . Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011; 43(10):1022-5. PMC: 3184199. DOI: 10.1038/ng.912. View

Henley S, Larson T, Wu M, Antao V, Lewis M, Pinheiro G . Mesothelioma incidence in 50 states and the District of Columbia, United States, 2003-2008. Int J Occup Environ Health. 2013; 19(1):1-10. PMC: 4406225. DOI: 10.1179/2049396712Y.0000000016. View

Tanaka S, Choe N, Hemenway D, Zhu S, Matalon S, Kagan E . Asbestos inhalation induces reactive nitrogen species and nitrotyrosine formation in the lungs and pleura of the rat. J Clin Invest. 1998; 102(2):445-54. PMC: 508904. DOI: 10.1172/JCI3169. View

Lantos J, Foldi V, Roth E, Weber G, Bogar L, Csontos C . Burn trauma induces early HMGB1 release in patients: its correlation with cytokines. Shock. 2009; 33(6):562-7. DOI: 10.1097/SHK.0b013e3181cd8c88. View

Lin H, Shen Y, Long H, Wang H, Luo Z, Wei Z . Performance of osteopontin in the diagnosis of malignant pleural mesothelioma: a meta-analysis. Int J Clin Exp Med. 2014; 7(5):1289-96. PMC: 4073746. View

Jube S, Rivera Z, Bianchi M, Powers A, Wang E, Pagano I . Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. 2012; 72(13):3290-301. PMC: 3389268. DOI: 10.1158/0008-5472.CAN-11-3481. View

Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M . High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 2003; 48(4):971-81. DOI: 10.1002/art.10859. View

10.

Flores R, Pass H, Seshan V, Dycoco J, Zakowski M, Carbone M . Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg. 2008; 135(3):620-6, 626.e1-3. DOI: 10.1016/j.jtcvs.2007.10.054. View

11.

Kaya H, Demir M, Taylan M, Sezgi C, Tanrikulu A, Yilmaz S . Fibulin-3 as a diagnostic biomarker in patients with malignant mesothelioma. Asian Pac J Cancer Prev. 2015; 16(4):1403-7. DOI: 10.7314/apjcp.2015.16.4.1403. View

12.

Qi F, Okimoto G, Jube S, Napolitano A, Pass H, Laczko R . Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling. Am J Pathol. 2013; 183(5):1654-66. PMC: 3814524. DOI: 10.1016/j.ajpath.2013.07.029. View

13.

Yang H, Rivera Z, Jube S, Nasu M, Bertino P, Goparaju C . Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc Natl Acad Sci U S A. 2010; 107(28):12611-6. PMC: 2906549. DOI: 10.1073/pnas.1006542107. View

14.

Kirschner M, Pulford E, Hoda M, Rozsas A, Griggs K, Cheng Y . Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis. Br J Cancer. 2015; 113(6):963-9. PMC: 4578085. DOI: 10.1038/bjc.2015.286. View

15.

Napolitano A, Pellegrini L, Dey A, Larson D, Tanji M, Flores E . Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2015; 35(15):1996-2002. PMC: 5018040. DOI: 10.1038/onc.2015.243. View

16.

Palmblad K, Schierbeck H, Sundberg E, Horne A, Harris H, Henter J . High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome. Mol Med. 2014; 20:538-47. PMC: 4365070. DOI: 10.2119/molmed.2014.00183. View

17.

Pass H, Lott D, Lonardo F, Harbut M, Liu Z, Tang N . Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med. 2005; 353(15):1564-73. DOI: 10.1056/NEJMoa051185. View

18.

Ge X, Antoine D, Lu Y, Arriazu E, Leung T, Klepper A . High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD). J Biol Chem. 2014; 289(33):22672-22691. PMC: 4132775. DOI: 10.1074/jbc.M114.552141. View

19.

Youden W . Index for rating diagnostic tests. Cancer. 1950; 3(1):32-5. DOI: 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3. View

20.

Hashim D, Boffetta P . Occupational and environmental exposures and cancers in developing countries. Ann Glob Health. 2014; 80(5):393-411. DOI: 10.1016/j.aogh.2014.10.002. View