scholarly journals Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma

Science ◽  
2014 ◽  
Vol 343 (6174) ◽  
pp. 1010-1014 ◽  
Author(s):  
J. N. Honeyman ◽  
E. P. Simon ◽  
N. Robine ◽  
R. Chiaroni-Clarke ◽  
D. G. Darcy ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chimeric Transcript ◽  
Fibrolamellar Hepatocellular Carcinoma

Characterization of a novel mutation in fibrolamellar hepatocellular carcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 284-284
Author(s):  
Kevin M Riggle ◽  
Heidi Kenerson ◽  
Machiko Kazami ◽  
Renay Bauer ◽  
Raymond Sze Yeung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Normal Liver ◽  
Kinase Assay ◽  
Mutant Protein ◽  
Intrinsic Activity ◽  
Chimeric Transcript ◽  
Wild Type ◽  
Fibrolamellar Hepatocellular Carcinoma ◽  
Mutant Transcript ◽  
Elevated Expression

284 Background: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a subtype of HCC occurring in children and young adults in the absence of underlying liver disease. Currently, there is no effective therapy for unresectable or metastatic FL-HCC. Recent genomic analysis identified a consistent mutation in FL-HCC involving a deletion on chromosome 19 resulting in a chimeric transcript containing the 5’-region of a heat shock protein (DNAJB1) fused to the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant protein and its effects on PKA activity in human FL-HCC. Methods: We prepared tissue lysates from four snap-frozen FL-HCC samples with paired, non-tumor liver as well as adult HCCs. PKA activity was determined via a radioactive kinase assay in the presence and absence of cAMP, a PKA activator. RNA was extracted using TRIZOL, and used for qRT-PCR. Triple immuno-fluorescent labeling was performed using antibodies to PRKACA, PKA RIIα, and a nuclear marker, DRAQ5. Results: We found that expression of the chimeric transcript was increased 40-fold in FL-HCC compared to normal liver, and was significantly higher than that of wild-type DNAJB1 and PRKACA in FL-HCC. The corresponding mutant protein was highly expressed in the tumors and was unique to FL-HCC. Basal PKA activities from freshly lysed tumors and paired livers were not significantly different, but cAMP-stimulated PKA activity was significantly higher in FL-HCC tumors when compared to normal liver. Using multi-color immuno-fluorescence we detected mutant DNAJB1-PRKACA within the nucleus, while wild-type PRKACA localizes to the cytoplasm. Conclusions: The expression of DNAJB1-PRKACA is unique to FL-HCC and not found in classic forms of HCC. Markedly elevated expression of the mutant transcript is indicative of dysregulated DNAJB1 promoter activity. PKA activity in FL-HCCs remains cAMP-dependent, but is greatly enhanced in the presence of cAMP; this could reflect an altered intrinsic activity of the mutant protein and/or elevated expression. Further, the mutant protein showed aberrant localization to the nucleus. These findings suggest that DNAJB1-PRKACA in FL-HCC leads to over-activation of PKA, which may contribute to tumor development.

scholarly journals Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

2015 ◽  
Vol 112 (44) ◽  
pp. E5916-E5925 ◽  
Author(s):  
Elana P. Simon ◽  
Catherine A. Freije ◽  
Benjamin A. Farber ◽  
Gadi Lalazar ◽  
David G. Darcy ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcriptome Sequencing ◽  
Normal Tissue ◽  
Kinase Activity ◽  
Aurora Kinase ◽  
Chimeric Transcript ◽  
Fibrolamellar Hepatocellular Carcinoma ◽  
False Discovery ◽  
Kinase A

Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥1, false discovery rate ≤0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention.

Fibrolamellar hepatocellular carcinoma in Mexican patients

2002 ◽  
Vol 8 (2) ◽  
pp. 133-137 ◽  
Author(s):  
Julian Arista-Nasr ◽  
Lisa Gutierrez-Villalobos ◽  
Juan Nuncio ◽  
Hector Maldonaldo ◽  
Leticia Bornstein-Quevedo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fibrolamellar Hepatocellular Carcinoma ◽  
Mexican Patients

scholarly journals Immunohistochemical detection of procalcitonin in fibrolamellar hepatocellular carcinoma

2021 ◽  
Author(s):  
Kotaro Matsumoto ◽  
Kentaro Kikuchi ◽  
Ayako Hara ◽  
Hiromichi Tsunashima ◽  
Koichi Tsuneyama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histopathological Examination ◽  
Epigastric Pain ◽  
Positive Staining ◽  
C Reactive Protein ◽  
Fibrolamellar Hepatocellular Carcinoma ◽  
Tumor Biopsy ◽  
Reactive Protein ◽  
Right Lobe ◽  
The Right

AbstractA 25-year-old woman with fever and epigastric pain was referred to our hospital. Blood examination showed significant liver dysfunction, markedly high C-reactive protein (CRP 19.1 mg/dL) and procalcitonin (48.3 ng/mL) levels. Dynamic computed tomography showed a tumor approximately 120 mm in size in the right lobe of the liver, but with no abscess formation. The patient was hospitalized and started on antibiotics; her CRP level improved, but the procalcitonin level did not decrease. Histopathological examination of the liver tumor biopsy revealed fibrolamellar hepatocellular carcinoma (FLC). Positive staining of the FLC with an anti-procalcitonin antibody suggested the production of procalcitonin.

scholarly journals Imaging of fibrolamellar hepatocellular carcinoma

1988 ◽  
Vol 151 (2) ◽  
pp. 295-299 ◽  
Author(s):  
DJ Brandt ◽  
CD Johnson ◽  
DH Stephens ◽  
LH Weiland
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fibrolamellar Hepatocellular Carcinoma
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