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Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma
Sarinya Kongpetch1,2, Apinya Jusakul1,3, Jing Quan Lim4,5
1Cholangiocarcinoma Screening and Care Program and Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
Purpose:
Cholangiocarcinoma (CCA) remains a disease with poor prognosis and limited therapeutic options. Identification of driver genetic alterations may lead to the discovery of more effective targeted therapies. CCAs harboring FGFR2 fusions have recently demonstrated promising responses to FGFR inhibitors, highlighting their potential relevance as predictive biomarkers. CCA incidence is high in the northeast of Thailand and its neighboring countries because of chronic infection with the liver fluke Opisthorchis viverrini (Ov). However, there are currently no available data on the prevalence of FGFR alterations in fluke-associated CCA in endemic countries.
Materials And Methods:
In this study, we performed anchored multiplex polymerase chain reaction target enrichment RNA sequencing of FGFR1-3, validated by fluorescence in situ hybridization and Sanger sequencing, in 121 Ov-associated and 95 non-Ov-associated CCA tumors.
Results:
Compared with non-fluke-associated CCA (11/95; 11.6%), FGFR2 fusions were significantly less common in fluke-associated CCA (1/121; 0.8%; P = .0006). All FGFR fusions were detected exclusively in intrahepatic CCAs and were mutually exclusive with KRAS/ERBB2/BRAF/FGFR mutations, pointing to their potential roles as oncogenic drivers.
Conclusion:
FGFR2 fusions are rare in fluke-associated CCA, underscoring how distinct etiologies may affect molecular landscapes in tumors and highlighting the need to discover other actionable genomic alterations in endemic fluke-associated CCA.
Insights
Fibroblast growth factor receptor 2 (FGFR2) fusions are rare in liver fluke-associated cholangiocarcinoma (CCA). This highlights how different causes of CCA can alter its molecular profile, necessitating new therapeutic targets for fluke-associated tumors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Cholangiocarcinoma (CCA) has a poor prognosis and limited treatment options.
- Identifying driver genetic alterations is key to developing targeted therapies.
- FGFR2 fusions in CCA show promise for FGFR inhibitor therapies, acting as predictive biomarkers.
Purpose of the Study:
- To investigate the prevalence of FGFR alterations in fluke-associated CCA.
- To compare FGFR alterations between CCA tumors associated with liver fluke (Opisthorchis viverrini) and those without.
- To understand the molecular landscape of CCA in endemic regions.
Main Methods:
- Anchored multiplex PCR target enrichment RNA sequencing of FGFR1-3 was performed on 121 Opisthorchis viverrini-associated and 95 non-associated CCA tumors.
- Fluorescence in situ hybridization and Sanger sequencing were used for validation.
Main Results:
- FGFR2 fusions were significantly less common in fluke-associated CCA (0.8%) compared to non-fluke-associated CCA (11.6%).
- All detected FGFR fusions occurred exclusively in intrahepatic CCAs.
- FGFR fusions were mutually exclusive with KRAS, ERBB2, BRAF, and FGFR mutations.
Conclusions:
- FGFR2 fusions are rare in CCA linked to liver fluke infections.
- Tumor etiology significantly impacts molecular characteristics.
- Further research is needed to identify actionable genomic alterations in endemic fluke-associated CCA.
