Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma
Summary: Background: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accur...
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Elsevier
2018-04-01
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Abderrahim Oussalah Susann Rischer Mouni Bensenane Guillaume Conroy Pierre Filhine-Tresarrieu Renée Debard Denise Forest-Tramoy Thomas Josse Dana Reinicke Matthieu Garcia Amandine Luc Cédric Baumann Ahmet Ayav Valérie Laurent Marcus Hollenbach Cristina Ripoll Rosa-Maria Guéant-Rodriguez Fares Namour Alexander Zipprich Michael Fleischhacker Jean-Pierre Bronowicki Jean-Louis Guéant |
spellingShingle |
Abderrahim Oussalah Susann Rischer Mouni Bensenane Guillaume Conroy Pierre Filhine-Tresarrieu Renée Debard Denise Forest-Tramoy Thomas Josse Dana Reinicke Matthieu Garcia Amandine Luc Cédric Baumann Ahmet Ayav Valérie Laurent Marcus Hollenbach Cristina Ripoll Rosa-Maria Guéant-Rodriguez Fares Namour Alexander Zipprich Michael Fleischhacker Jean-Pierre Bronowicki Jean-Louis Guéant Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma EBioMedicine |
author_facet |
Abderrahim Oussalah Susann Rischer Mouni Bensenane Guillaume Conroy Pierre Filhine-Tresarrieu Renée Debard Denise Forest-Tramoy Thomas Josse Dana Reinicke Matthieu Garcia Amandine Luc Cédric Baumann Ahmet Ayav Valérie Laurent Marcus Hollenbach Cristina Ripoll Rosa-Maria Guéant-Rodriguez Fares Namour Alexander Zipprich Michael Fleischhacker Jean-Pierre Bronowicki Jean-Louis Guéant |
author_sort |
Abderrahim Oussalah |
title |
Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma |
title_short |
Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma |
title_full |
Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma |
title_fullStr |
Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma |
title_full_unstemmed |
Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma |
title_sort |
plasma msept9: a novel circulating cell-free dna-based epigenetic biomarker to diagnose hepatocellular carcinoma |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2018-04-01 |
description |
Summary: Background: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9) for diagnosing HCC among cirrhotic patients. Methods: We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study) and Germany (replication study). All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test. Findings: We included 289 patients with cirrhosis (initial: 186; replication: 103), among whom 98 had HCC (initial: 51; replication: 47). The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC) of 0.944 (0.900–0.970, p < 0.0001) in the initial study (replication: 0.930 [0.862–0.971, p < 0.0001]; meta-analysis: AUROC = 0.940 [0.910–0.970, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.67; and no publication bias). In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis (initial: OR = 6.30, for each mSEPT9 positive triplicate [2.92–13.61, p < 0.0001]; replication: OR = 6.07 [3.25–11.35, p < 0.0001]; meta-analysis: OR = 6.15 [2.93–9.38, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.95; no publication bias). AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930–0.989) and 0.942 (0.878–0.978), respectively, with a pooled AUROC of 0.962 ([0.937–0.987, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.36; and no publication bias). Interpretation: Among patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC. Keywords: Cirrhosis, Hepatocellular carcinoma, Circulating cell-free DNA-based epigenetic biomarker, DNA methylation, mSEPT9 |
url |
http://www.sciencedirect.com/science/article/pii/S2352396418301166 |
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doaj-53b5425db50f47b4b3ebfbee63e14fd12020-11-25T02:47:35ZengElsevierEBioMedicine2352-39642018-04-0130138147Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular CarcinomaAbderrahim Oussalah0Susann Rischer1Mouni Bensenane2Guillaume Conroy3Pierre Filhine-Tresarrieu4Renée Debard5Denise Forest-Tramoy6Thomas Josse7Dana Reinicke8Matthieu Garcia9Amandine Luc10Cédric Baumann11Ahmet Ayav12Valérie Laurent13Marcus Hollenbach14Cristina Ripoll15Rosa-Maria Guéant-Rodriguez16Fares Namour17Alexander Zipprich18Michael Fleischhacker19Jean-Pierre Bronowicki20Jean-Louis Guéant21Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France; INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France; Corresponding author at: Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France.First Department of Internal Medicine, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), GermanyDepartment of Hepatology and Gastroenterology, University Hospital of Nancy, Nancy F-54000, FranceDepartment of Hepatology and Gastroenterology, University Hospital of Nancy, Nancy F-54000, FranceDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France; INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, FranceDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, FranceDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, FranceDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, FranceFirst Department of Internal Medicine, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), GermanyDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, FranceESPRI-BioBase Unit, Methodological and Biostatistical Support Unit, Platform of Clinical Research Support PARC, University Hospital of Nancy, Nancy F-54000, FranceESPRI-BioBase Unit, Methodological and Biostatistical Support Unit, Platform of Clinical Research Support PARC, University Hospital of Nancy, Nancy F-54000, FranceDepartment of Digestive, Hepatobiliary and Endocrine Surgery, University Hospital of Nancy, Nancy, F-54000, FranceDepartment of Radiology, University Hospital of Nancy, Nancy, F-54000, FranceDivision of Gastroenterology and Rheumatology, Department of Medicine, Dermatology and Neurology, University of Leipzig, Liebigstraße 20, D-04103 Leipzig, GermanyFirst Department of Internal Medicine, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), GermanyDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France; INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, FranceDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France; INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, FranceFirst Department of Internal Medicine, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), GermanyFirst Department of Internal Medicine, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), GermanyINSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France; Department of Hepatology and Gastroenterology, University Hospital of Nancy, Nancy F-54000, FranceDepartment of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France; INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France; Department of Hepatology and Gastroenterology, University Hospital of Nancy, Nancy F-54000, France; Corresponding author at: Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France.Summary: Background: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9) for diagnosing HCC among cirrhotic patients. Methods: We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study) and Germany (replication study). All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test. Findings: We included 289 patients with cirrhosis (initial: 186; replication: 103), among whom 98 had HCC (initial: 51; replication: 47). The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC) of 0.944 (0.900–0.970, p < 0.0001) in the initial study (replication: 0.930 [0.862–0.971, p < 0.0001]; meta-analysis: AUROC = 0.940 [0.910–0.970, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.67; and no publication bias). In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis (initial: OR = 6.30, for each mSEPT9 positive triplicate [2.92–13.61, p < 0.0001]; replication: OR = 6.07 [3.25–11.35, p < 0.0001]; meta-analysis: OR = 6.15 [2.93–9.38, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.95; no publication bias). AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930–0.989) and 0.942 (0.878–0.978), respectively, with a pooled AUROC of 0.962 ([0.937–0.987, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.36; and no publication bias). Interpretation: Among patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC. Keywords: Cirrhosis, Hepatocellular carcinoma, Circulating cell-free DNA-based epigenetic biomarker, DNA methylation, mSEPT9http://www.sciencedirect.com/science/article/pii/S2352396418301166 |