Fibrolamellar Carcinoma in the Carney Complex: PRKAR1A Loss Instead of the Classic DNAJB1-PRKACA Fusion

Abstract

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 400kb 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. Since 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 3 tumors displayed the typical morphology of fibrolamellar carcinoma and were positive for Arginase, CK7 and CD68. FISH was negative for PRKACA rearrangements. However, PRKAR1A sequencing identified pathogenic mutations in two of two cases with successful sequencing. In addition, all 3 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 that was negative for PRKACA rearrangements but had loss of PRKAR1A protein expression as well as PRKAR1A mutations.

In 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. This article is protected by copyright. All rights reserved.

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