Detection of a Recurrent
            <i>DNAJB1-PRKACA</i>
            Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma

Honeyman, Joshua N.; Simon, Elana P.; Robine, Nicolas; Chiaroni-Clarke, Rachel; Darcy, David G.; Lim, Irene Isabel P.; Gleason, Caroline E.; Murphy, Jennifer; Rosenberg, Brad R.; Teegan, Lydia; Takacs, Constantin N.; Botero, Sergio Botero; Belote, R.L.; Germer, Søren; Emde, Anne-Katrin; Vacic, Vladimir; Bhanot, Umesh; LaQuaglia, Michael P.; Simon, Sanford M.

doi:10.1126/science.1249484

Cited by 407 publications

(462 citation statements)

References 46 publications

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“…However, a recent study of 10 fibrolamellar carcinoma cases identified a recurrent somatic intrachromosomal deletion on chromosome 19, leading to a DNAJB1-PRKACA fusion transcript. 3 Our study confirms the presence of the DNAJB1-PRKACA fusion in a further 26 fibrolamellar carcinomas. Together, these data are an independent confirmation of 100% sensitivity of this fusion for fibrolamellar carcinoma.…”

Section: Discussionsupporting

confidence: 73%

“…1 Interestingly, this general constellation of findings (young age, lack of underlying disease, and morphological monotony) is a common feature of translocation-associated tumors 2 and a recurrent chimeric gene was recently identified in the fibrolamellar carcinoma. 3 However, the specificity of this fusion in the context of other primary hepatic neoplasms is unknown. To address this question and to develop clinically applicable test platforms, we developed an RT-PCR assay for use with paraffin-embedded tissues along with a FISH assay, both of which can detect the novel fusion at the transcriptional and genomic level, respectively.…”

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confidence: 99%

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DNAJB1-PRKACA is specific for fibrolamellar carcinoma

et al. 2015

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Fibrolamellar carcinoma is a distinct subtype of hepatocellular carcinoma that predominantly affects young patients without underlying cirrhosis. A recurrent DNAJB1-PRKACA fusion has recently been reported in fibrolamellar carcinomas. To determine the specificity of this fusion and to develop routinely available clinical methods of detection, we developed an RT-PCR assay for paraffin-embedded tissues and a FISH probe for detection of the rearrangements of the PRKACA locus. We also developed an RNA in situ hybridization assay to assess expression levels of the total chimeric transcript and wild-type transcripts. A total of 106 primary liver tumors were studied by RT-PCR, including 26 fibrolamellar carcinomas (4 of which were metastases to the abdominal wall or lymph nodes), 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24/26) and the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types. FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas, which can closely mimic fibrolamellar carcinoma. Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens, but in none of the scirrhous hepatocellular carcinomas. Finally, a RNA in situ hybridization strategy was positive in 7/7 successfully hybridized cases, and showed mRNA over-expression in all of the fibrolamellar carcinomas. In addition, the stromal cells embedded in the characteristic intratumoral fibrosis of fibrolamellar carcinomas and the background liver tissues were negative for the DNAJB1-PRKACA fusion by all tested methods. In conclusion, detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

et al. 2015

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“…In addition, this fusion protein serves as a therapeutic target for the successful drug imatinib (4). In solid human tumors, fusion genes such as the TMPRSS2-ERG fusion in prostate cancer (5), FGFR-TACC in glioblastoma (6), and DNAJB1-PRKACA in liver cancer (7) are important molecular signatures for understanding cancer mechanisms and stratifying patient groups.…”

mentioning

confidence: 99%

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Kannan

Coarfa

Chao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.cancer-specific fusion gene | high-grade serous ovarian cancer | AKT2 | BCAM | fusion kinase O varian cancer is responsible for the death of ∼140,200 women yearly, and 70% of these deaths are due to the high-grade serous ovarian cancer (HGSC) subtype (1), which is typically detected only after it has metastasized. Genomic characterization of HGSC tumors shows that TP53 mutations are present in 96% and BRCA1/2 in 22% of HGSC (2). These mutations are thought to occur early in pathogenesis (3) and promote genomic instability, thus giving rise to the high degree of heterogeneity and genomic rearrangements that are characteristic of these cancers. The characteristic genome rearrangements in HGSC imply that recombination events such as gene fusions should be common. Moreover, if the activity of a fusion gene represents a common oncogenic mechanism, the same fusion gene is likely to occur in many patients.Recurrent fusion genes are important for understanding cancer mechanisms and developing useful clinical biomarkers and anticancer therapies. For instance, the BCR-ABL fusion gene in chronic myeloid leukemia is known to initiate oncogenesis through formation of a misregulated BCR-ABL fusion kinase. The BCR-ABL fusion gene is also a clinical biomarker of high diagnostic and prognostic utility in chronic myeloid leukemia. In addition, this fusion protein serves as a therapeutic target for the successful drug imatinib (4). In solid human tumors, fusion genes such as the TMPRSS2-ERG fusion in prostate cancer (5), FGFR-TACC in glioblastoma (6), and DNAJB1...

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“…In contrast, HNF1-α mutations have not been identified in genomic or transcriptomic study of fibrolamellar carcinomas. 2,19,20 This suggests an alternate mechanism for the downregulation of LFABP in fibrolamellar carcinoma, perhaps through methylation or microRNAs. The mosaic pattern seen in some of the fibrolamellar carcinomas is also unusual, with scattered strongly positive tumor cells in a background of more diffuse loss of staining in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…The carcinoma is histologically distinct and shows a consistent somatic deletion leading to DNAJB1-PRKACA fusion transcripts. 1,2 Although the tumorigenic mechanism for this fusion protein is not yet proven, the fusion protein appears to drive overexpression of PRKACA. PRKACA is one of the catalytic subunits of protein kinase A, a key regulatory kinase with numerous downstream signaling targets.…”

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confidence: 99%

Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss

et al. 2016

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Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-α inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n = 19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-α inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-α inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-α inactivation is an important event in fibrolamellar carcinoma pathogenesis.

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

Cited by 407 publications

References 46 publications

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss

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