DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma

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Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.

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The authors gratefully acknowledge the members of the Molecular Diagnostics Service in the Department of Pathology. The authors also thank Dr. Achim Jungbluth for his assistance with arginase immunohistochemical stain and albumin mRNA in-situ hybridization and Ms. Jordana Shapiro for her assistance with the figures.

The authors are aware of another study also demonstrating PRKACA fusions in oncocytic neoplasms of the pancreatobiliary tree, which provides further confirmation of our findings (Singhi AD, Wood LD, Parks E et al. Recurrent PRKACA and PRKACB Gene Rearrangements Drive Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct. Gastroenterology. Accepted for publication).


This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, by the Melamed Family Foundation, and by the National Cancer Institute Cancer Center Core Grant No. P30-CA008748.

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Correspondence to Olca Basturk.

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Vyas, M., Hechtman, J.F., Zhang, Y. et al. DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. Mod Pathol (2019) doi:10.1038/s41379-019-0398-2

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