Fibrolamellar
carcinomas are characterized by activation of
protein kinase A, a
kinase composed of catalytic and regulatory subunits. PRKACA encodes a catalytic subunit of
protein kinase A, and almost all fibrolamellar
carcinomas have a heterozygous 400-kb deletion that leads to the fusion of DNAJB1 and PRKACA. The resulting DNAJB1-PRKACA fusion transcript is believed to activate
protein kinase A by dysregulation of the catalytic portion of the
protein. In contrast, PRKAR1A 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 PRKAR1A 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 in situ hybridization was negative for PRKACA rearrangements. However, PRKAR1A 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 PRKACA rearrangements but had loss of PRKAR1A
protein expression as well as PRKAR1A mutations.
CONCLUSION: Fibrolamellar
carcinoma can be part of the
Carney complex; in this setting, fibrolamellar
carcinomas have inactivating PRKAR1A mutations instead of the DNAJB1-PRKACA fusion gene found in sporadic fibrolamellar
carcinomas, providing an alternate means for activation of
protein kinase A. (Hepatology 2017).