Osteopontin and latent‐TGF β binding‐protein 2 as potential diagnostic markers for HBV‐related hepatocellular carcinoma
Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low‐resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that...
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| Published in | International journal of cancer Vol. 136; no. 1; pp. 172 - 181 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Wiley
01.01.2015
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low‐resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α‐Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low‐resource contexts. Deep‐plasma proteome analysis was performed in HCC patients, patients with CLD and in HB‐carrier controls from Thailand (South‐East Asia) and The Gambia (West‐Africa). Mass spectrometry profiling identified latent‐transforming growth factor β binding‐protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker‐based detection of HBV‐related HCC.
What's new?
Chronic infection with hepatitis B virus (HBV) is the main risk factor for chronic liver disease and hepatocellular carcinoma (HCC) in many low‐resource countries, where diagnosis is constrained by lack of clinical, histopathological, and biomarker resources. Here, deep‐plasma proteomics was used to identify candidate biomarkers for HCC diagnosis. Validation studies on a total of 684 samples showed that elevated levels of LTBP2 and/or OPN are highly specific and sensitive markers for distinguishing HCC from chronic liver disease. LTBP2 appears highly associated with HBV‐related HCC, while OPN shows a robust and consistent association with HCC in both HBV and HCV contexts. |
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| AbstractList | Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC.Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform alpha -Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor beta binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. What's new? Chronic infection with hepatitis B virus (HBV) is the main risk factor for chronic liver disease and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological, and biomarker resources. Here, deep-plasma proteomics was used to identify candidate biomarkers for HCC diagnosis. Validation studies on a total of 684 samples showed that elevated levels of LTBP2 and/or OPN are highly specific and sensitive markers for distinguishing HCC from chronic liver disease. LTBP2 appears highly associated with HBV-related HCC, while OPN shows a robust and consistent association with HCC in both HBV and HCV contexts. Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep plasma proteome analysis was performed in HCC patients, patients with chronic liver disease (CLD) and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified Latent-Transforming Growth Factor β Binding-Protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analysed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve (ROC) of 0.85 in distinguishing HCC from CLD in subjects with α-Fetoprotein (AFP) < 20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low‐resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α‐Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low‐resource contexts. Deep‐plasma proteome analysis was performed in HCC patients, patients with CLD and in HB‐carrier controls from Thailand (South‐East Asia) and The Gambia (West‐Africa). Mass spectrometry profiling identified latent‐transforming growth factor β binding‐protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker‐based detection of HBV‐related HCC. What's new? Chronic infection with hepatitis B virus (HBV) is the main risk factor for chronic liver disease and hepatocellular carcinoma (HCC) in many low‐resource countries, where diagnosis is constrained by lack of clinical, histopathological, and biomarker resources. Here, deep‐plasma proteomics was used to identify candidate biomarkers for HCC diagnosis. Validation studies on a total of 684 samples showed that elevated levels of LTBP2 and/or OPN are highly specific and sensitive markers for distinguishing HCC from chronic liver disease. LTBP2 appears highly associated with HBV‐related HCC, while OPN shows a robust and consistent association with HCC in both HBV and HCV contexts. Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. © 2014 UICC. Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. |
| Author | Guilloreau, Paule Camey, Suzy Mendy, Maimuna Shin, Hai‐Rim Oh, Jin‐Kyoung Costa, Andre Nogueira Lesi, Olufunmilayo A. Beretta, Laura Chang, Hee‐Kyung Hainaut, Pierre Sangrajrang, Suleeporn Plymoth, Amelie Lee, Duk‐Hee Kirk, Gregory D. Khuhaprema, Thiravud Merle, Philippe Santos‐Silva, Daniela Ortiz‐Cuaran, Sandra |
| AuthorAffiliation | 4 Department of Statistics, Institute of Mathematics, Federal University of Rio Grande do Sul, Brazil 6 National Cancer Institute, Bangkok, Thailand 13 Centre de Recherche en Cancérologie de Lyon (CRCL) UMR INSERM 1052, Lyon, France 15 International Prevention Research Institute, Lyon, France 12 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA 3 Graduate Program in Epidemiology, Faculty of Medicine, Federal University of Rio Grande do Sul, Brazil 11 World Health Organization, Western Pacific Regional Office, Manila, Philippines 2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 14 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 8 Kosin Medical Centre, Busan, Republic of Korea 5 Croix-Rousse Hospital, Lyon, France 9 National Cancer Center, Republic of Korea 10 Kyungpook National University, Daegu, Republic of Korea 7 Department of Medicine, University of L |
| AuthorAffiliation_xml | – name: 4 Department of Statistics, Institute of Mathematics, Federal University of Rio Grande do Sul, Brazil – name: 5 Croix-Rousse Hospital, Lyon, France – name: 14 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA – name: 2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden – name: 11 World Health Organization, Western Pacific Regional Office, Manila, Philippines – name: 1 International Agency for Research on Cancer, Lyon, France – name: 6 National Cancer Institute, Bangkok, Thailand – name: 15 International Prevention Research Institute, Lyon, France – name: 9 National Cancer Center, Republic of Korea – name: 13 Centre de Recherche en Cancérologie de Lyon (CRCL) UMR INSERM 1052, Lyon, France – name: 3 Graduate Program in Epidemiology, Faculty of Medicine, Federal University of Rio Grande do Sul, Brazil – name: 7 Department of Medicine, University of Lagos Teaching Hospital, Lagos, Nigeria – name: 12 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA – name: 8 Kosin Medical Centre, Busan, Republic of Korea – name: 10 Kyungpook National University, Daegu, Republic of Korea |
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| Keywords | chronic liver disease LTBP2 biomarkers osteopontin hepatocellular carcinoma Chronic/blood Humans Latent TGF-beta Binding Proteins/blood Liver Neoplasms/blood/diagnosis/virology Osteopontin/blood Poverty ROC Curve Ltbp2 biomarkers chronic liver disease hepatocellular carcinoma osteopontin Area Under Curve Biomarkers Tumor/blood Carcinoma Hepatocellular/blood/diagnosis/virology Case-Control Studies Early Detection of Cancer Hepatitis B |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC4617682 Present address: International Prevention Research Institute, Lyon, France Present address: Department of Translational Genomics, University of Cologne, Köln, Germany Present address: Mechanistic Toxicology and Molecular Pathology, Non-Clinical Department, UCB Pharma, S.A., Braine L'Alleud, Belgium |
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| References | 2010; 11 2009; 24 2011; 119 2011; 53 2011; 31 2011; 10 2008; 103 2011; 19 2011; 6 2012; 55 2011; 7 2010; 61 2013; 19 2004; 110 2012; 130 2011; 129 2010; 24 2004; 39 2008; 49 2009; 221 2008; 116 2008; 135 2005; 37 2010; 2011 2001; 34 2008; 62 2010; 4 2006; 101 2009; 15 2009; 18 2007; 26 2003; 163 |
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| SubjectTerms | Area Under Curve biomarkers Biomarkers, Tumor - blood Carcinoma, Hepatocellular - blood Carcinoma, Hepatocellular - diagnosis Carcinoma, Hepatocellular - virology Case-Control Studies chronic liver disease Early Detection of Cancer Hepatitis B virus Hepatitis B, Chronic - blood Hepatitis C virus hepatocellular carcinoma Humans Latent TGF-beta Binding Proteins - blood Life Sciences Liver Neoplasms - blood Liver Neoplasms - diagnosis Liver Neoplasms - virology LTBP2 osteopontin Osteopontin - blood Poverty ROC Curve |
| Title | Osteopontin and latent‐TGF β binding‐protein 2 as potential diagnostic markers for HBV‐related hepatocellular carcinoma |
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