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Published on: September 30, 2019
FGFR1 and FGFR2 in fibrolamellar carcinoma
Rondell P Graham1, Joaquin J Garcia1, Patricia T Greipp1
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Aims:
Fibrolamellar carcinoma is characterized by a recurrent DNAJB1-PRKACA chimeric transcript. The functional properties of the fusion are unknown, but are believed to include PRKACA up-regulation. PRKCA is a subunit of protein kinase A. The downstream targets of protein kinase A are unknown, but may include interactions with fibroblast growth factor receptor (FGFR) pathways. In addition, inhibitors for FGFR proteins have been developed recently.
Methods And Results:
Nineteen histologically confirmed fibrolamellar carcinomas were studied. All showed the characteristic DNAJB1-PRKACA transcript by reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemistry for FGFR1 was negative in 19 of 19 cases using a monoclonal antibody, while a polyclonal antibody showed no expression (n = 11) or weak and focal expression (n = 8). RNAin-situ hybridization was 2+ in two cases, 1+ in four cases and negative in four cases. FGFR1 fluorescence in-situ hybridization (FISH) revealed polysomy of chromosome 8 in 17 of 19 cases. Break-apart FISH for FGFR2 was negative for rearrangements in 12 of 12 informative cases.
Conclusions:
Fibrolamellar carcinomas show polysomy of chromosome 8 and the FGFR1 locus, and only modest mRNA expression and weak or absent expression at the protein level. FGFR2 rearrangement was not detected. These data reduce the likelihood that FGFR inhibitors will be effective in the treatment of most fibrolamellar carcinomas.
Insights
Fibrolamellar carcinoma, linked to a DNAJB1-PRKACA transcript, shows chromosome 8 polysomy but not FGFR2 rearrangements. This suggests fibroblast growth factor receptor (FGFR) inhibitors may not be effective treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fibrolamellar carcinoma (FLC) is a rare liver cancer.
- FLC is characterized by the DNAJB1-PRKACA chimeric transcript.
- The functional role of this fusion and its downstream targets, potentially involving fibroblast growth factor receptor (FGFR) pathways, remain unclear.
Purpose of the Study:
- To investigate the expression and genetic status of FGFR1 and FGFR2 in fibrolamellar carcinoma.
- To assess the potential of FGFR-targeted therapies for FLC.
Main Methods:
- Studied 19 fibrolamellar carcinoma cases.
- Utilized reverse transcription-polymerase chain reaction (RT-PCR) for transcript analysis.
- Employed immunohistochemistry, RNA in-situ hybridization, and fluorescence in-situ hybridization (FISH) for FGFR1 and FGFR2 analysis.
Main Results:
- All cases exhibited the DNAJB1-PRKACA transcript.
- FGFR1 protein expression was weak or absent in all cases.
- FGFR1 locus polysomy on chromosome 8 was observed in 17/19 cases.
- No FGFR2 rearrangements were detected in informative cases.
Conclusions:
- Fibrolamellar carcinomas frequently display chromosome 8 polysomy and FGFR1 locus polysomy.
- Modest mRNA and weak/absent protein expression of FGFR1 suggest limited therapeutic potential.
- The absence of FGFR2 rearrangements further reduces the likelihood of FGFR inhibitor efficacy in most FLC cases.
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