Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion
Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion
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DOI：
10.1002/hep.29719
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发表时间：
2018-10-01
期刊：
影响因子：
13.5
通讯作者：
Torbenson, Michael S.
中科院分区：
文献类型：
--
作者：
Graham, Rondell P.;Lackner, Carolin;Torbenson, Michael S.
纤维板层癌的特征是蛋白激酶A的活化，这是一种由催化和调节亚基组成的激酶。PRKACA编码蛋白激酶a的一个催化亚基，几乎所有的纤维板层癌都有一个400 kb的杂合缺失，导致DNAJB1和PRKACA融合。由此产生的DNAJB1-PRKACA融合转录物被认为通过蛋白质催化部分的失调激活蛋白激酶A。相反，PRKAR1A编码蛋白激酶A的一个调节亚基。我们假设该调节单位的功能丧失也可能导致蛋白激酶A激活，从而导致纤维板层癌。由于PRKAR1A突变是卡尼复合体的基础，我们在卡尼复合体个体中寻找肝脏肿瘤。我们确定了3人与纤维板层癌和卡尼复合体的个人历史。所有3例肿瘤均表现为典型的纤维板层癌形态，精氨酸酶、细胞角蛋白7和分化簇68阳性。荧光原位杂交检测PRKACA重排阴性。然而，PRKAR1A测序在两个成功测序的病例中发现了两个致病突变。此外，所有3例患者PRKAR1A蛋白表达均为阴性，这与蛋白激酶a的关键调控单元失活一致。我们还在一名没有卡尼复合体病史的患者中发现了另一例纤维板层癌，该患者PRKACA重排阴性，但PRKAR1A蛋白表达缺失，PRKAR1A突变。结论：纤维板层癌可能是卡尼复合体的一部分；在这种情况下，纤维板层癌具有失活的PRKAR1A突变，而不是散发性纤维板层癌中发现的DNAJB1-PRKACA融合基因，为蛋白激酶a的激活提供了另一种方法（Hepatology, 2017）。
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).