Heterogeneous phenotypes of Pten-null hepatocellular carcinoma in hepatitis B virus transgenic mice parallels liver lobule zonal gene expression patterns

Chronic HBV infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The phenotypes of HCC are diverse, in part, due to mutations in distinct oncogenes and/or tumor suppressor genes. These genetic drivers of HCC development have generally been considered as major mediators of tumor heterogeneity. Using the liver-specific Pten-null HBV transgenic mouse model of chronic viral infection, a critical role for liver lobule zone-specific gene expression patterns in determining HCC phenotype is demonstrated. These observations suggest that the position of the hepatocyte within the liver lobule, and hence its intrinsic gene expression pattern at the time of cellular transformation, make critical contributions to the properties of the resulting liver tumor. These results may explain why therapies targeting pathways modulated by specific identified tumor driver genes display variable treatment efficacy. Overall design: Amplicon bisulfite-sequencing data: 12 samples. RNA-seq: 8 samples. Samples are DNA (for methylation analysis) and RNA (for RNA-seq analysis) samples from control HBV(+/-)Pten(fl/fl)Cre(+/-) [normal liver] and HBV(+/-)Pten(fl/fl)Cre(+/-) [paired Pten-null non-tumor and tumor HCC samples] livers.