{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T21:29:06Z","timestamp":1790458146416,"version":"4.1.0"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T00:00:00Z","timestamp":1525996800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T00:00:00Z","timestamp":1525996800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:p>\n                    Fibrolamellar carcinomas are characterized by activation of protein kinase A, a kinase composed of catalytic and regulatory subunits.\n                    <jats:italic toggle=\"yes\">PRKACA<\/jats:italic>\n                    encodes a catalytic subunit of protein kinase A, and almost all fibrolamellar carcinomas have a heterozygous 400\u2010kb deletion that leads to the fusion of\n                    <jats:italic toggle=\"yes\">DNAJB1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">PRKACA<\/jats:italic>\n                    . The resulting\n                    <jats:italic toggle=\"yes\">DNAJB1\u2010PRKACA<\/jats:italic>\n                    fusion transcript is believed to activate protein kinase A by dysregulation of the catalytic portion of the protein. In contrast,\n                    <jats:italic toggle=\"yes\">PRKAR1A<\/jats:italic>\n                    encodes one of the regulatory subunits of protein kinase A. We hypothesized that loss of function of this regulatory unit could also lead to protein kinase A activation and thus to fibrolamellar carcinoma. Because\n                    <jats:italic toggle=\"yes\">PRKAR1A<\/jats:italic>\n                    mutations underlie the Carney complex, we searched for liver tumors in individuals with the Carney complex. We identified 3 individuals with fibrolamellar carcinomas and a personal history of the Carney complex. All three tumors displayed the typical morphology of fibrolamellar carcinoma and were positive for arginase, cytokeratin 7, and cluster of differentiation 68. Fluorescence\n                    <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                    hybridization was negative for\n                    <jats:italic toggle=\"yes\">PRKACA<\/jats:italic>\n                    rearrangements. However,\n                    <jats:italic toggle=\"yes\">PRKAR1A<\/jats:italic>\n                    sequencing identified pathogenic mutations in two of two cases with successful sequencing. In addition, all three cases were negative for PRKAR1A protein expression, consistent with inactivation of this key regulatory unit of protein kinase A. We also identified one additional fibrolamellar carcinoma in an individual without a documented history of the Carney complex who was negative for\n                    <jats:italic toggle=\"yes\">PRKACA<\/jats:italic>\n                    rearrangements but had loss of PRKAR1A protein expression as well as\n                    <jats:italic toggle=\"yes\">PRKAR1A<\/jats:italic>\n                    mutations.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Fibrolamellar carcinoma can be part of the Carney complex; in this setting, fibrolamellar carcinomas have inactivating\n                    <jats:italic toggle=\"yes\">PRKAR1A<\/jats:italic>\n                    mutations instead of the\n                    <jats:italic toggle=\"yes\">DNAJB1\u2010PRKACA<\/jats:italic>\n                    fusion gene found in sporadic fibrolamellar carcinomas, providing an alternate means for activation of protein kinase A. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2017).\n                  <\/jats:p>","DOI":"10.1002\/hep.29719","type":"journal-article","created":{"date-parts":[[2017,12,9]],"date-time":"2017-12-09T10:17:02Z","timestamp":1512814622000},"page":"1441-1447","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":67,"title":["Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1\u2010PRKACA fusion"],"prefix":"10.1097","volume":"68","author":[{"given":"Rondell P.","family":"Graham","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Lackner","sequence":"additional","affiliation":[{"name":"Institute of Pathology,Medical University of Graz,Graz,Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Terracciano","sequence":"additional","affiliation":[{"name":"Molecular Pathology Division,University Hospital Basel,Basel,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yessica","family":"Gonz\u00e1lez\u2010Cant\u00fa","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Biol\u00f3gicas,Universidad Aut\u00f3noma de Nuevo Le\u00f3n,Nuevo Le\u00f3n,Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Maleszewski","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia T.","family":"Greipp","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanford M.","family":"Simon","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Biophysics,The Rockefeller University,New York,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Torbenson","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,5,11]]},"reference":[{"key":"hep29719-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1053\/j.semdp.2016.12.010","article-title":"Fibrolamellar carcinoma: a histologically unique tumor with unique molecular findings","volume":"34","year":"2017","journal-title":"Semin Diagn Pathol"},{"key":"hep29719-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/1097-0142(19800715)46:2<372::AID-CNCR2820460227>3.0.CO;2-S","article-title":"Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico\u2010pathologic features","volume":"46","year":"1980","journal-title":"Cancer"},{"key":"hep29719-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/modpathol.2010.207","article-title":"Fibrolamellar carcinomas are positive for CD68","volume":"24","year":"2011","journal-title":"Mod Pathol"},{"key":"hep29719-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1126\/science.1249484","article-title":"Detection of a recurrent DNAJB1\u2010PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma","volume":"343","year":"2014","journal-title":"Science"},{"key":"hep29719-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/modpathol.2015.4","article-title":"DNAJB1\u2010PRKACA is specific for fibrolamellar carcinoma","volume":"28","year":"2015","journal-title":"Mod Pathol"},{"key":"hep29719-bib-0006-20241017","first-page":"E5916","article-title":"Transcriptomic characterization of fibrolamellar hepatocellular carcinoma","volume":"112","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep29719-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"44653","DOI":"10.1038\/srep44653","article-title":"Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non\u2010coding RNA signature of fibrolamellar carcinoma","volume":"7","year":"2017","journal-title":"Sci Rep"},{"key":"hep29719-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.gene.2015.11.052","article-title":"Protein kinase A catalytic subunit isoform PRKACA; 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