Integrative Analysis of DNA Methylation and Gene Expression Patterns in Tissues from Hepatocellular Carcinoma Patients

Abstract

Compared to European Americans (EAs), the incidence of Hepatocellular Carcinoma (HCC) is higher in African Americans (AAs) and is associated with more advanced tumor stage at diagnosis and lower survival rates. Despite the importance of DNA methylation in neoplastic transformation, the mechanisms of epigenetic disparity between AAs and EAs are yet to be fully realized in HCC. In this paper we present an integrated analysis of genome-wide DNA methylation and gene expression in a racially diverse cohort of 16 HCC patients using the Illumina MethylationEPIC BeadChip and HiSeq 4000 platforms. A mixed-effects ANOVA model was applied to compare molecular changes between tumors and adjacent non-cancerous liver tissues. In an effort to control for underlying variation in tumor composition, we used DNA methylation to assess measurements of tumor purity and adjusted our analysis to account for potential bias due to cell mixture effects. As a result, we were able to identify 17,249 differentially methylated regions (DMRs) and 981 differentially methylated and expressed genes (DM+DE) associated with HCC. Further, 14,912 DMRs and 637 DM+DE genes were identified as being associated with the EA race and 3,257 DMRs and 156 DM+DE genes identified as being associated with the AA race in HCC. We were able to identify 20 candidate genes as potential tumor suppressors in HCC, including TBX15, IGF1R, WDR66, ITPKB, CFTR, KCNA3, CXCL12, EA-specific MT1L, PIK23R5, and AA-specific GHR and ADRA2B. In summary, we have identified differentially methylated and expressed markers of HCC that are specific to AA and EA racial groups. These findings offer insights into the molecular mechanisms of epigenetic regulation in HCC progression as well as identify potential markers to address racial disparity in precision therapy and diagnosis.