Genome-Wide DNA Methylation Profiling Reveals Ancestry-Associated Epigenetic Reprogramming in Cervical...

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Cervical cancer (CC) disproportionately affects women of African ancestry (AA) compared to European ancestry (EA) women.
• Persistent high-risk human papillomavirus (HPV) infection is a key cause, but epigenetic reprogramming is implicated in ancestry-associated CC pathogenesis disparities.

Purpose of the Study:

• To investigate genome-wide DNA methylation differences in HPV-positive cervical intraepithelial neoplasia (CIN) lesions between women of AA and EA.
• To identify epigenetic mechanisms contributing to CC health disparities.

Main Methods:

• Genome-wide DNA methylation profiling was performed on CIN lesions from AA (n=15) and EA (n=15) women.
• Differential methylation analysis and pathway enrichment analyses were conducted.
• Protein expression and 5-hydroxymethylcytosine (5hmC) levels were assessed.

Main Results:

• Distinct epigenomic landscapes were identified in AA-CIN lesions, with widespread promoter hypermethylation and hypomethylation.
• Dysregulated pathways included ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling.
• Hypermethylation of tumor suppressor genes SH3GL2 and ARHGAP25 in AA lesions correlated with loss of protein expression and global 5hmC reduction.

Conclusions:

• Early, ancestry-specific epigenetic modifications contribute to CC health disparities by targeting tumor suppressor pathways and influencing oncogenic signaling.
• SH3GL2 and ARHGAP25 hypermethylation are potential biomarkers for CC disparities.
• Epigenetic regulation plays a significant role in the disparate progression of CC in AA women.