DNAJB1‐PKRACA ‐ A Novel PKa Fusion Protein That Drives Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver tumor that usually occurs in adolescents and young adults. Characterized by hepatocytes with deeply eosinophilic, granular cytoplasm interspersed with fibrous bands, FLHCC is without signs of cirrhosis as in Hepatocellular Carcinoma. To characterize its molecular pathogenesis, we performed RNA‐seq and whole genome sequencing of FLHCC paired with normal liver from the same patient. The majority of the DNA was unremarkable with few recurrent mutations or structural variants such as amplifications or inversions. The exception was a heterogeneous deletion of ~400 kB in one copy of chromosome 19. This produced a chimeric transcript and a fusion between the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A (PRKACA) which retained full enzymatic activity. This chimera has been found in every patient (n>200). Differential expression analysis of RNA‐seq revealed many changes in the gene expression in FLHCC. These were generally consistent between patients with FLHCC and different from HCC samples from the TCGA or published reports of other cancers. Some of the 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. Support or Funding Information The Rockefeller University Center for Clinical and Translational Science Grant 2UL1RR024143, The Sohn Foundation, The Rockefeller University, The Fibrolamellar Cancer Foundation