Putative Imprinting Control Regions with Aberrant Blood-Based DNA Methylation are Associated with Hepatocellular...

Area of Science:

• Epigenetics
• Genomics
• Oncology

Background:

• Site-specific 5-methylcytosine levels in blood can serve as surrogate markers for epigenetic alterations in inaccessible tissues.
• Aberrant DNA methylation is linked to hepatocellular carcinoma (HCC) risk, but replication has been limited by low genomic coverage and tissue-specific methylation.
• Imprinting control regions (ICRs) exhibit stable, early-onset methylation across tissues, suggesting their aberrant methylation in blood may indicate liver disease.

Purpose of the Study:

• To identify imprinting control regions (ICRs) with aberrant DNA methylation associated with hepatocellular carcinoma (HCC) using primary HCC samples.
• To inform the development of a blood-based risk stratification panel for earlier HCC detection and clinical triage.

Main Methods:

• Whole genome bisulfite sequencing (WGBS) was performed on leukocyte-derived DNA from 10 primary HCC cases and 51 controls to identify differential methylation.
• An independent validation cohort of 29 primary HCC cases and 36 controls used the Human Imprintome Methylation Array to confirm differential methylation in leukocytes.

Main Results:

• WGBS identified 1,519 differentially methylated regions associated with HCC, mapping to 81 putative ICRs, many novel to HCC.
• A total of 97 putative ICRs were identified, including 16 previously associated with HCC or precancerous liver disease states.
• Validation confirmed 46 (57%) of these regions, with nearest genes enriched for liver disease-related pathways.

Conclusions:

• Comprehensive genome profiling revealed aberrant methylation at putative ICRs in blood associated with HCC.
• These findings support the investigation of ICRs as stable, tissue-independent biomarkers for early blood-based HCC detection.