Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.

Abstract

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 <i>FGFR2</i> 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 <i>Opisthorchis viverrini</i> (Ov). However, there are currently no available data on the prevalence of <i>FGFR</i> alterations in fluke-associated CCA in endemic countries. In this study, we performed anchored multiplex polymerase chain reaction target enrichment RNA sequencing of <i>FGFR1-3</i>, validated by fluorescence in situ hybridization and Sanger sequencing, in 121 Ov-associated and 95 non-Ov-associated CCA tumors. Compared with non-fluke-associated CCA (11/95; 11.6%), <i>FGFR2</i> fusions were significantly less common in fluke-associated CCA (1/121; 0.8%; <i>P</i> = .0006). All <i>FGFR</i> fusions were detected exclusively in intrahepatic CCAs and were mutually exclusive with <i>KRAS/ERBB2/BRAF/FGFR</i> mutations, pointing to their potential roles as oncogenic drivers. <i>FGFR2</i> 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.