Epigenomic Landscape of Hepatocellular Carcinoma in Nigerian Patients: Integrating ATAC-seq, ChIP-seq, and Whole-Methylome Profiling

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and carries extremely poor prognosis in Nigeria, where it typically presents at advanced stages against a background of chronic HBV infection and aflatoxin B1 exposure. The epigenomic landscape of HCC in African patients, shaped by these specific etiological drivers, remains almost entirely uncharacterized. This dissertation presents the first integrated epigenomic characterization of HCC in Nigerian patients, employing ATAC-seq (chromatin accessibility), ChIP-seq (H3K27ac and H3K4me3 histone modifications), and whole-genome bisulfite sequencing (WGBS) on matched tumor and adjacent non-tumor liver tissue. Tissue samples were obtained through surgical resection and core needle biopsy at Lagos University Teaching Hospital and University College Hospital Ibadan, Southwest Nigeria. Twenty-four HCC cases with documented HBV status and aflatoxin B1-associated TP53 R249S mutation were included. Bioinformatic integration employed the ENCODE uniform processing pipeline, and regulatory element-gene target linking used the Activity-By-Contact (ABC) model. ATAC-seq revealed 3,412 differentially accessible chromatin regions (DARs) in HCC tissue, with gained accessibility enriched at oncogenic transcription factor motifs (FOXA1, HNF4A, MYC). HBV-positive tumors exhibited a distinct enhancer activation signature at AFP and GPC3 loci compared to HBV-negative cases. WGBS identified 9,847 differentially methylated regions (DMRs), with aflatoxin B1-associated HCC showing preferential hypermethylation at tumor suppressor promoters RASSF1A, CDKN2A, and PTEN. The multi-layer epigenomic integration identified 14 super-enhancers uniquely gained in Nigerian HCC with no counterpart in TCGA HCC data, suggesting Africa-specific oncogenic regulatory programs. Keywords: hepatocellular carcinoma, ATAC-seq, ChIP-seq, whole-methylome, Lagos.