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

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Abstract

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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References

  1. 1.

    Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim II, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343:1010–4.

  2. 2.

    Graham RP, Jin L, Knutson DL, Kloft-Nelson SM, Greipp PT, Waldburger N, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015;28:822–9.

  3. 3.

    Simon EP, Freije CA, Farber BA, Lalazar G, Darcy DG, Honeyman JN, et al. Transcriptomic characterization of fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci USA. 2015;112:E5916–25.

  4. 4.

    Graham RP. Fibrolamellar Carcinoma: what is new and why it matters. Surg Pathol Clin. 2018;11:377–87.

  5. 5.

    Adsay NV, Adair CF, Heffess CS, Klimstra DS. Intraductal oncocytic papillary neoplasms of the pancreas. Am J Surg Pathol. 1996;20:980–94.

  6. 6.

    Basturk O, Tan M, Bhanot U, Allen P, Adsay V, Scott SN, et al. The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes. Mod Pathol. 2016;29:1058–69.

  7. 7.

    Wang T, Askan G, Adsay V, Allen P, Jarnagin WR, Memis B, et al. Intraductal oncocytic papillary neoplasms: clinical-pathologic characterization of 24 cases, with an emphasis on associated invasive carcinomas. Am J Surg Pathol. 2019;43:656–61.

  8. 8.

    Wang T, Askan G, Zehir A, Adsay N, Akturk G, Bhanot U, et al. Mass-forming intraductal neoplasms of the biliary tract comprise morphologically and genetically distinct entities (abstract). Mod Pathol. 2018;31:1927A.

  9. 9.

    Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64.

  10. 10.

    Middha S, Zhang L, Nafa K, Jayakumaran G, Wong D, Kim HR, et al. Reliable Pan-Cancer Microsatellite Instability Assessment by Using Targeted Next-Generation Sequencing Data. JCO Precis Oncol. 2017;2017. https://doi.org/10.1200/PO.17.00084.

  11. 11.

    Shen R, Seshan VE. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016;44:e131.

  12. 12.

    Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Lynch KD, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20:1479–84.

  13. 13.

    Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13.

  14. 14.

    Benayed R, Offin M, Mullaney K, Sukhadia P, Rios K, Desmeules P, et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res. 2019;25:4712–22.

  15. 15.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.

  16. 16.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

  17. 17.

    Askan G, Deshpande V, Klimstra DS, Adsay V, Sigel C, Shia J, et al. Expression of markers of hepatocellular differentiation in pancreatic acinar cell neoplasms: a potential diagnostic pitfall. Am J Clin Pathol. 2016;146:163–9.

  18. 18.

    Reid LM, Sethupathy P. The DNAJB1-PRKACA chimera: candidate biomarker and therapeutic target for fibrolamellar carcinomas. Hepatology. 2016;63:662–4.

  19. 19.

    Xu L, Hazard FK, Zmoos AF, Jahchan N, Chaib H, Garfin PM, et al. Genomic analysis of fibrolamellar hepatocellular carcinoma. Hum Mol Genet. 2015;24:50–63.

  20. 20.

    Engelholm LH, Riaz A, Serra D, Dagnaes-Hansen F, Johansen JV, Santoni-Rugiu E, et al. CRISPR/Cas9 engineering of adult mouse liver demonstrates that the Dnajb1-Prkaca gene fusion is sufficient to induce tumors resembling fibrolamellar hepatocellular carcinoma. Gastroenterology. 2017;153:1662–73 e10.

  21. 21.

    Kastenhuber ER, Lalazar G, Houlihan SL, Tschaharganeh DF, Baslan T, Chen CC, et al. DNAJB1-PRKACA fusion kinase interacts with beta-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci USA. 2017;114:13076–84.

  22. 22.

    Tomasini MD, Wang Y, Karamafrooz A, Li G, Beuming T, Gao J, et al. Conformational landscape of the PRKACA-DNAJB1 chimeric kinase, the driver for fibrolamellar hepatocellular carcinoma. Sci Rep. 2018;8:720.

  23. 23.

    Dinh TA, Jewell ML, Kanke M, Francisco A, Sritharan R, Turnham RE, et al. MicroRNA-375 suppresses the growth and invasion of fibrolamellar carcinoma. Cell Mol Gastroenterol Hepatol. 2019;7:803–17.

  24. 24.

    Graham RP, Garcia JJ, Greipp PT, Barr Fritcher EG, Kipp BR, Torbenson MSFGFR1. FGFR1 and FGFR2 in fibrolamellar carcinoma. Histopathology. 2016;68:686–92.

  25. 25.

    Graham RP, Lackner C, Terracciano L, Gonzalez-Cantu Y, Maleszewski JJ, Greipp PT, et al. Fibrolamellar carcinoma in the carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology. 2018;68:1441–7.

  26. 26.

    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10.

  27. 27.

    Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci. 2018;109:1282–91.

  28. 28.

    Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusulehto A, et al. Response to ERBB3-Directed targeted therapy in NRG1-rearranged cancers. Cancer Disco. 2018;8:686–95.

  29. 29.

    Reid MD, Stallworth CR, Lewis MM, Akkas G, Memis B, Basturk O, et al. Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: Criteria and clinical implications of accurate diagnosis. Cancer Cytopathol. 2016;124:122–34.

  30. 30.

    Farhi DC, Shikes RH, Silverberg SG. Ultrastructure of fibrolamellar oncocytic hepatoma. Cancer. 1982;50:702–9.

  31. 31.

    Thomson M. Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria. Cell Mol Life Sci. 2002;59:213–9.

  32. 32.

    Ward SC, Huang J, Tickoo SK, Thung SN, Ladanyi M, Klimstra DS. Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation. Mod Pathol. 2010;23:1180–90.

  33. 33.

    Lin CC, Yang HM. Fibrolamellar Carcinoma: a concise review. Arch Pathol Lab Med. 2018;142:1141–5.

  34. 34.

    Basturk O, Chung SM, Hruban RH, Adsay NV, Askan G, Iacobuzio-Donahue C, et al. Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas. Virchows Arch. 2016;469:523–32.

  35. 35.

    Martin RC, Klimstra DS, Schwartz L, Yilmaz A, Blumgart LH, Jarnagin W. Hepatic intraductal oncocytic papillary carcinoma. Cancer. 2002;95:2180–7.

  36. 36.

    Lalazar G, Simon SM. Fibrolamellar carcinoma: recent advances and unresolved questions on the molecular mechanisms. Semin Liver Dis. 2018;38:51–9.

  37. 37.

    Casi Pharmaceuticals. Update on phase 2 trial of ENMD-2076 in fibrolamellar carcinoma. Casi Pharmaceuticals. http://www.casipharmaceuticals.com/investor-relations/news/casi-pharmaceuticals-provides-update-on-phase-2-trial-of-enmd-2076.

  38. 38.

    Kastenhuber ER, Craig J, Ramsey J, Sullivan KM, Sage J, De Oliveira S, et al. Road map for fibrolamellar carcinoma: progress and goals of a diversified approach. J Hepatocell Carcinoma. 2019;6:41–8.

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Acknowledgements

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).

Funding

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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