Abstract 685: Integrative screening of DNA methylation markers enables early detection of hepatocellular carcinoma

Abstract DNA methylation, a pivotal epigenetic modification regulating gene expression, has gained significant attention as a potential diagnostic biomarker for various cancers, including hepatocellular carcinoma (HCC). This study aimed to identify aberrant DNA methylation patterns and protein alterations using integrated methodologies and to develop a robust biomarker panel for blood-based early detection of HCC. Genome-wide methylation profiling was performed to identify hypermethylated CpG sites and genes that distinguish early-stage HCC from non-HCC tissues. Using four distinct strategies, 44 candidate marker genes were identified and subsequently assessed in combination with five protein markers in a cohort of 299 blood samples. Through 5-fold cross-validation, a panel comprising six methylation markers from four different groups achieved an area under the curve (AUC) of 0.938, outperforming panels derived from single-group markers. A final 6-marker panel, combining four methylation markers and two protein markers in a logistic regression (LR) model, was developed. This panel demonstrated a sensitivity of 92.2% at a specificity of 94.3% in the training set, and a sensitivity of 86.4% at a specificity of 97.8% in the validation set. Notably, the 6-marker panel showed superior sensitivity (75.0%) for detecting HCC at Barcelona Clinic Liver Cancer (BCLC) stages 0-A compared to alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP). A multi-group approach to selecting methylation markers outperformed single-group strategies. The developed 6-marker panel demonstrates excellent sensitivity and specificity, offering a promising tool for the early detection of HCC, particularly in its earliest stages. Citation Format: Hao Zhuang, Bo Wang, Yongmei Li. Integrative screening of DNA methylation markers enables early detection of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 685.