Hlady, Ryan A.

Abstract Dysregulation of the intrinsic DNA methylation landscape is a ubiquitous feature of human carcinogenesis, manifested by global hypomethylation and promoter-specific hypermethylation, ultimately resulting in genome instability and tumor suppressor gene silencing, respectively. Alterations in DNA methylation are particularly apparent in hepatocellular carcinoma (HCC) which afflicts roughly 750,000 new patients each year [1]. Indeed, it has been demonstrated that a variety of tumor suppressor genes (e.g. p53, E-cadherin) are hypermethylated and silenced in HCC [2-4]. Importantly, HCC is accompanied by the premalignant stage of cirrhosis in 80% of cases. One major roadblock to understanding the methylome in HCC is the presence of multiple etiologies such as Hepatitis C virus (HCV), Hepatitis B virus (HBV), and chronic alcoholism. Therefore, we performed genome-wide methylation profiling to dissect the methylation patterns of more than 170 primary liver samples to stratify etiologic and stage-specific changes in the DNA methylation landscape. Our results profile the DNA methylation landscape across normal, cirrhotic, and HCC livers in the largest study of its kind to date. We unveil distinct locus-specific and large-scale effects of HCV, HBV, and chronic alcoholism in hepatocarcinogenesis. Furthermore, analysis indicates a specific methylation profile for individual etiologies as well as conserved patterns throughout cirrhosis and hepatocellular carcinoma. Our study demonstrates that each etiology contains potential biomarkers and targets for downstream clinical therapeutics. This study is our first step toward defining the epigenome in cirrhosis and hepatocellular carcinoma and will be combined with future genomic and epimutational data (e.g. transcription, histone modifications, miRNA) to determine the true extent and interplay between epigenetic marks across different stages of liver cancer. Overall, this research has the potential to improve our understanding of epigenetics and result in diagnostic, prognostic, and therapeutic epigenetic signatures in cirrhosis and hepatocellular carcinoma, which are expected to allow for more timely and efficient detection of disease. 1. Jemal, A., et al., Global cancer statistics. CA: a cancer journal for clinicians, 2011. 61(2): p. 69-90. 2. Tischoff, I. and A. Tannapfe, DNA methylation in hepatocellular carcinoma. World journal of gastroenterology : WJG, 2008. 14(11): p. 1741-8. 3. Calvisi, D.F., et al., Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. The Journal of clinical investigation, 2007. 117(9): p. 2713-22. 4. Lambert, M.P., et al., Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. Journal of hepatology, 2011. 54(4): p. 705-15. Citation Format: Ryan A. Hlady, Rochelle Tiedemann, William Puszyk, Chen Liu, Jeong-Hyeon Choi, Keith D. Robertson. Identification of common and unique epigenetic signatures of chronic hepatitis infection and alcohol abuse in human liver disease. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2309. doi:10.1158/1538-7445.AM2014-2309