Abstract 3937: Global methylation patterns, genome copy number alterations and expression analysis distinguish two distinct subclasses of hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is a devastating disease ranking as the third most frequent cause of cancer deaths worldwide. In the US, the incidence of HCC tripled between 1975 and 2005 and at present day survival rates are as low as 20% due to limited treatment options. Future therapeutic advances rely on a greater understanding of the full range of genetic and epigenetic defects displayed by this cancer. Recent advances in whole genome methylation profiling have allowed us to investigate these alterations in a cohort of HCC and normal liver samples. Methods: Using the Illumina Infinium platform, we analyzed the methylation patterns in over 50 human HCC and normal liver samples obtained from surgical resection and transplant specimens. We also investigated the expression and gene copy number (CGH) status on the same cohort using the Agilent platform. Findings: We have been able to identify two very distinct groups of HCC based on their methylation status. In each class of tumors, there are both hypo- and hypermethylated genes relative to normal liver. Several of these tumor-specific alterations have been validated by pyrosequencing. In one class of tumors, many genes that are normally repressed by polycomb group proteins in stem cells are hypermethylated, consistent with the tumor cell of origin being a progenitor stem cell. The other class of tumors does not show this association and are likely to originate from a different cell of origin. Intriguingly, these two classes also correspond to distinct groups based on both DNA copy number analysis and expression analysis. Conclusion: Combining these three independent methods of global analysis; expression profiling, epigenome analysis and CGH data, we have identified a robust new classification scheme for HCC. This approach should provide insight for future therapeutic advances. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3937. doi:10.1158/1538-7445.AM2011-3937