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Updated: Aug 26, 2025
Analyzing Tumor Gene Expression Factors with the CorExplorer Web Portal
Published on: October 11, 2019
FGFR mRNA Expression in Cholangiocarcinoma and Its Correlation with FGFR2 Fusion Status and Immune Signatures
Vishwajith Sridharan1,2, Azfar Neyaz1, Abhijit Chogule1
1Mass General Cancer Center, Boston, Massachusetts.
Purpose:
Selective FGFR inhibitors are effective against cholangiocarcinomas that harbor gene alterations in FGFR2. Clinical trials suggest that expression of wild-type FGFR mRNA can predict sensitivity to FGFR inhibitors, but this biomarker has not been well characterized in cholangiocarcinoma. This study explores the prevalence of FGFR mRNA overexpression in cholangiocarcinoma, its role in predicting sensitivity to FGFR inhibitors, and its association with immune markers.
Experimental Design:
Tissue microarrays of intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC) resected between 2004 and 2015 were used to evaluate FGFR1-4 mRNA expression levels by RNA in situ hybridization (ISH). Expression levels of FGFR2 mRNA were correlated with FGFR2 fusion status and with patient outcomes. Immune markers expression was assessed by IHC and CSF1 and CSF1 receptor expression were examined by RNA ISH.
Results:
Among 94 patients with resected cholangiocarcinoma, the majority had ICC (77%). FGFR2 fusions were identified in 23% of ICCs and 5% of ECCs. High levels of FGFR mRNA in FGFR2 fusion-negative ICC/ECC were seen for: FGFR1 (ICC/ECC: 15%/0%), FGFR2 (ICC/ECC: 57%/0%), FGFR3 (ICC/ECC: 53%/18%), and FGFR4 (ICC/ECC: 32%/0%). Overall, 62% of fusion-negative cholangiocarcinomas showed high levels of FGFR mRNA. In patients with advanced FGFR2 fusion-positive ICC, high levels of FGFR2 mRNA did not correlate with clinical benefit. FGFR2 fusion-positive tumors showed a paucity of PD-L1 on tumor cells.
Conclusions:
FGFR mRNA overexpression occurs frequently in cholangiocarcinoma in the absence of genetic alterations in FGFR. This study identifies a molecular subpopulation in cholangiocarcinoma for which further investigation of FGFR inhibitors is merited outside currently approved indications.
Insights
Fibroblast growth factor receptor (FGFR) mRNA overexpression is common in cholangiocarcinoma, even without FGFR gene alterations. This finding suggests potential new uses for FGFR inhibitors in treating this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Selective fibroblast growth factor receptor (FGFR) inhibitors show efficacy in cholangiocarcinomas with FGFR2 gene alterations.
- Wild-type FGFR mRNA expression is a potential biomarker for FGFR inhibitor sensitivity, but requires further characterization in cholangiocarcinoma.
Purpose of the Study:
- To investigate the prevalence of FGFR mRNA overexpression in cholangiocarcinoma.
- To determine the role of FGFR mRNA overexpression in predicting sensitivity to FGFR inhibitors.
- To assess the association between FGFR mRNA expression and immune markers.
Main Methods:
- RNA in situ hybridization (ISH) was used to evaluate FGFR1-4 mRNA expression in tissue microarrays of intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC).
- FGFR2 mRNA levels were correlated with FGFR2 fusion status and patient outcomes.
- Immunohistochemistry (IHC) and RNA ISH were employed to assess immune markers, including CSF1 and CSF1 receptor.
Main Results:
- FGFR2 fusions were present in 23% of ICCs and 5% of ECCs.
- High FGFR mRNA levels were observed in 62% of fusion-negative cholangiocarcinomas across FGFR1, FGFR2, FGFR3, and FGFR4.
- In FGFR2 fusion-positive ICC, high FGFR2 mRNA did not correlate with clinical benefit, and these tumors showed low PD-L1 expression.
Conclusions:
- FGFR mRNA overexpression frequently occurs in cholangiocarcinoma independent of genetic alterations.
- A subset of cholangiocarcinomas with FGFR mRNA overexpression warrants further investigation for FGFR inhibitor therapy beyond current indications.
