DNA Methylation Profile in Buffy Coat Identifies Methylation Differences Between Cirrhosis with and Without Hepatocellular Carcinoma.

Simple Summary: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). HCC incidence and mortality have increased rapidly over the past two decades in the US, with a <20% 5-year survival rate. Understanding the mechanisms of this transition and identifying biomarkers is vital for effective screening and reducing HCC-related mortality. This study evaluated genome-wide DNA methylation patterns in the buffy coats of cirrhosis patients who developed HCC and those who remained HCC-free during an average four-year follow-up. We then identified differentially methylated sites, distinguishing cirrhosis with HCC from cirrhosis without HCC. The findings support the theory that buffy coat-derived DNA methylation markers could be implementable to stratify cirrhosis patients at high risk before clinical symptoms appear. Background/Objectives: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). Understanding the mechanisms leading to the transition from cirrhosis to HCC and identifying key biomarkers is crucial to developing effective screening strategies and reducing HCC-related mortality. DNA methylation is associated with gene inactivation and plays an important role in physiological and pathological processes; however, its role in cirrhosis progression to HCC is unknown. Methods: We performed genome-wide DNA methylation profiling using Illumina Infinium MethylationEPI BeadChip in pre-diagnostic samples from 22 cirrhosis patients who subsequently developed HCC and 22 cirrhosis patients who remained HCC-free during an average 4-year follow-up. In a secondary analysis, we examined a subset of patients without hepatitis C virus (HCV) infection. Results: We identified three differentially methylated positions (DMPs) located in ADAM12 (cg13674437) and PSD3 (cg06758847 and cg24595678) that show a strong association with HCC risk (lower median vs. higher median hazards ratio (HR): HR _cg13674437 = 0.34, 95% CI = 0.14–0.83; HR _cg06758847 = 4.89, 95% CI = 1.79–13.33; HR _cg24595678 = 11.19, 95% CI = 3.27–38.35). After excluding all HCV-active patients from our analysis, the HR for the DMPs remained significant. Conclusions: In conclusion, the findings in this study support the theory that buffy coat-derived DNA methylation markers could be used to identify biomarkers among cirrhosis patients at high risk for HCC before clinical symptoms appear. A further study with a large prospective cohort is required to validate these findings. [ABSTRACT FROM AUTHOR]