Abstract
BackgroundHepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, primarily due to failed early detection. HCC screening is recommended among individuals with cirrhosis using biannual abdominal ultrasound, for earlier tumor detection, administration of curative treatment, and improved survival. Surveillance by imaging with or without biomarkers such as alpha-fetoprotein (AFP) remains suboptimal for early stage HCC detection. Here we report on the development and assessment of methylation biomarkers from liquid biopsies for HCC surveillance in cirrhotic patients.MethodsDNA methylation markers including the HCCBloodTest (Epigenomics AG) and a DNA-methylation panel established by next generation sequencing (NGS) were assessed using a training/testing design. The NGS panel algorithm was established in a training study (41 HCC patients; 46 cirrhotic non-HCC controls). For testing, plasma samples were obtained from cirrhotic patients (Child class A or B) with (60) or without (103) early stage HCC (BCLC stage 0, A, B). The assays were then tested using blinded sample sets and analyzed by preset algorithms.ResultsThe HCCBloodTest and the NGS panel exhibited 76.7% and 57% sensitivities at 64.1% and 97% specificity, respectively. In a post-hoc analysis, a combination of the NGS panel with AFP (20 ng/mL) achieved 68% sensitivity at 97% specificity (AUC = 0.9).ConclusionsMethylation biomarkers in cell free plasma DNA provide a new alternative for HCC surveillance. Multiomic panels comprising DNA methylation markers with other biological markers, such as AFP, provide an option to further increase the overall clinical performance of surveillance via minimally invasive blood samples.Trial Registration: Test set study—ClinicalTrials.gov (NCT03804593) January 11, 2019, retrospectively registered.
Highlights
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, primarily due to failed early detection
Design The study was designed to determine the performance of methylated SEPTIN9 (mSEPT9) and a novel generation sequencing (NGS) DNA methylation panel as surveillance biomarkers for HCC detection in patients with cirrhosis
The biomarker panel was first established and the interpretive algorithm trained using plasma DNA samples from cirrhotic patients with and without cirrhosis. mSEPT9 was used in the HCCBloodTest format (Epigenomics AG Berlin Germany) following the instructions for use for the kit
Summary
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, primarily due to failed early detection. Given the size of the at risk cirrhotic population, the effort required for guideline recommended surveillance, the current suboptimal performance of recommended surveillance methods, and the low surveillance rates, there is a significant clinical need for novel minimally invasive testing to aid in the detection of HCC at an early stage. Efforts to address this need include discovery and development of novel biomarkers [7], and diagnostic algorithms combining biomarker data and patient features to improve performance. When used in combination with ultrasound (GALADUS) detection is further enhanced, though this observation requires further external validation [9]
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