Circulating Cell-free DNA-based Epigenetic Biomarker mSEPT9 for Hepatocellular Carcinoma Detection in Cirrhosis

Overview

Prospective evaluation of the circulating cell-free DNA-based epigenetic biomarker (mSEPT9) through a cross-sectional biomarker phase II design. The aim of the SEPT9-CROSS study is to assess the diagnostic accuracy of the plasma mSEPT9 biomarker in a large-scale study of 530 cirrhotic patients recruited in the Nancy University Hospital.

Full Title of Study: “Diagnostic Accuracy of the Circulating Cell-free DNA-based Epigenetic Biomarker mSEPT9 for Hepatocellular Carcinoma Detection Among Cirrhotic Patients: the SEPT9-CROSS Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Diagnostic
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: February 12, 2023

Detailed Description

Epigenetic alterations are a common hallmark of human cancer. Single epigenetic markers are starting to be incorporated into clinical practice; however, the translational use of these biomarkers has not been validated at the 'omics' level. This is strikingly the case in hepatocellular carcinoma (HCC) which represent the most common primary malignant tumor of the liver. Alpha-fetoprotein (AFP) has been widely used as a diagnostic marker of HCC; however, according to international guidelines (AASLD, EASL), AFP is unsufficiently sensitive or unsufficiently specific for use in a screening assay. Aberrantly methylated DNA sequences frequently occur in tumors and are detected in the circulation of cancer patients by polymerase chain reaction (PCR). SEPT9 is a significant epi-driver gene in liver carcinogenesis. The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with carcinogenesis. SEPT9 is involved in the onset of rat hepatocarcinogenesis and SEPT9-promoter hypermethylation was reported in HCC in man. SEPT9 expression is turned on in cells throughout the body and absent or diminished by aberrant promoter methylation in several types of cancer. Through an initial proof-of-concept pilot study from France and an independent replication study from Germany, we showed that the circulating cell-free DNA methylation-based epigenetic biomarker mSEPT9 is a promising plasma biomarker for diagnosing HCC in cirrhotic patients. The aim of the SEPT9-CROSS study is to confirm the diagnostic accuracy of the biomarker in a large-scale study of 530 cirrhotic patients recruited in the Nancy University Hospital.

Interventions

  • Diagnostic Test: “Epi proColon 2.0 CE” test from Epigenomics, Inc (Berlin, Germany)
    • The mSEPT9 assay consists of DNA extraction from plasma, bisulfite conversion of DNA, purification of bis-DNA, and real-time PCR.

Arms, Groups and Cohorts

  • Experimental: HCC-free cirrhotic patients (Controls)
    • Cirrhotic patients enrolled in an HCC screening program by abdominal ultrasound and AFP every six months and followed at the Department of Hepatology of the University Hospital of Nancy. Each patient included will undergo a diagnostic test called “Epi proColon 2.0 CE” from Epigenomics, Inc (Berlin, Germany) also known as Plasma mSEPT9 test.
  • Experimental: HCC-positive cirrhotic patients (Cases)
    • Cirrhotic patients followed at the Department of Hepatology of the University Hospital of Nancy who presents an HCC according to the AASLD guidelines. Each patient included will undergo a diagnostic test called “Epi proColon 2.0 CE” from Epigenomics, Inc (Berlin, Germany) also known as Plasma mSEPT9 test.

Clinical Trial Outcome Measures

Primary Measures

  • Presence of hepatocellular carcinoma.
    • Time Frame: The diagnosis of HCC will be based on overall patient’s evaluation including clinical, biological and imaging workup which will be carried out during the consultation and/or the three months preceding or following the inclusion consultation.
    • The diagnosis of hepatocellular carcinoma will be based on the guidelines of the American Association for the Study of Liver Diseases (AASLD) (Hepatology. 2011;53:1020-2). The adjudicating physicians will be blinded to patient results associated with the mSEPT9 test.

Secondary Measures

  • Presence of early hepatocellular carcinoma. Early hepatocellular carcinoma will be defined as a tumor smaller than 30 mm according to Kudo M (Liver Cancer. 2013;2:69-72).
    • Time Frame: The diagnosis will be based on an overall patient’s evaluation including clinical, biological and imaging workup which will be carried out during the consultation and/or the three months preceding or following the inclusion consultation.
    • The diagnosis of hepatocellular carcinoma will be based on the guidelines of the American Association for the Study of Liver Diseases (AASLD) (Hepatology. 2011;53:1020-2). The adjudicating physicians will be blinded to patient results associated with the mSEPT9 test.

Participating in This Clinical Trial

INCLUSION CRITERIA

  • Patient aged 18 and over. – Patient with a diagnosis of cirrhosis (alcohol, HBV, HBC, NASH, hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) with or without hepatocellular carcinoma (for each arm). – Affiliation to the French Social Security System (Health Insurance) NONINCLUSION CRITERIA FOR CASES : – Malignant liver tumor other than HCC: cholangiocarcinoma, hepatic metastasis of a carcinoma (e.g., colorectal adenocarcinoma); – History of HCC treated by surgical resection, focal destruction [radiofrequency, stereotactic radiotherapy (CYBERKNIFE®)], arterial chemoembolization, or radioembolization within the last five years. NONINCLUSION CRITERIA FOR CASES AND CONTROLS: – Legal protection measures; – Pregnant woman; – Hemodialysis, ongoing (possibility of interference with the test); – Presence of associated cancer (e.g., colorectal adenocarcinoma, urothelial carcinoma, breast carcinoma, etc.) since less than five years; – Presence of a hematological malignancy (no time limit).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Central Hospital, Nancy, France
  • Collaborator
    • Institut National de la Santé Et de la Recherche Médicale, France
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Abderrahim OUSSALAH, MD, PhD, Principal Investigator, University Hospital of Nancy, INSERM UMR_S 1256, Faculty of Medicine of Nancy, University of Lorraine
  • Overall Contact(s)
    • Abderrahim OUSSALAH, MD, PhD, +33 (0)3 83 15 36 29, a.oussalah@chru-nancy.fr

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