Abstract 4730: Molecular analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma

Genomic analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver tumor that usually occurs in adolescents and young adults. Originally considered a variant of hepatocellular carcinoma (HCC), FLHCC is characterized by hepatocytes with deeply eosinophilic, granular cytoplasm interspersed with fibrous bands, without signs of cirrhosis as in HCC. Since little is known of its molecular pathogenesis, we performed RNA-seq and whole genome sequencing of FLHCC paired with normal liver from the same patient. Our results demonstrated that the majority of the DNA is unremarkable with few recurrent mutations or structural variants such as amplifications or inversions The major finding is a heterogeneous deletion of ∼400 kB in chromosome 19 which produces a chimeric transcript and a fully functional protein, a fusion between the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A (PRKACA). Our initial observation of this chimera in 15 out of 15 patients has now been expanded to 116 out of 116 patients. Differential expression analysis of RNA-seq revealed many changes in the gene expression in FLHCC as compared to its paired normal liver. These changes were highly consistent from patient to patient, suggesting a unifying pathogenesis. The RNA-seq from our FLHCC samples had little in common with HCC samples from the TCGA or published reports of other cancers. An analysis of protein expression correlated well with the RNA-seq results. Some observed changes can directly be linked to increased activity of PRKACA. Other changes involve pathways known to participate in the initiation and progression of other cancers, which, along with an increase of PRKACA activity, represent targets for therapeutic intervention. Several of these targets are now being explored in cellular models, genetic, and PDX mouse models, as well as clinical trials. Citation Format: Elana P. Simon, Joshua N. Honeyman, David G. Darcy, Brad R. Rosenberg, Iris I. Lim, Jennifer M. Murphy, Ben Farber, Gadi Lalazar, Catherine Freije, Michael P. La Quaglia, Sanford M. Simon. Molecular analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4730. doi:10.1158/1538-7445.AM2015-4730