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Functional analysis of somatic mutations in tumorigenesis facilitates the development and optimization of personalized therapy for cancer patients. The <i>fibroblast growth factor receptor 2</i> (<i>FGFR2</i>) gene is frequently mutated in endometrial cancer (EC), but the functional implications of <i>FGFR2</i> mutations in cancer development remain largely unexplored. In this study, we introduced a reliable and readily deployable screening method to investigate the effects of <i>FGFR2</i> mutations. We demonstrated that distinct mutations in <i>FGFR2</i> can lead to differential downstream consequences, specifically affecting a disintegrin- and metalloprotease 17 (ADAM17)-dependent shedding of the epidermal growth factor receptor (EGFR) ligand heparin-binding EGF-like growth factor (HB-EGF) and phosphorylation of mitogen-activated protein kinases (MAPKs). Furthermore, we showed that the distribution of mutations within the <i>FGFR2</i> gene can influence their oncogenic effects. Together, these findings provide important insights into the complex nature of <i>FGFR2</i> mutations and their potential implications for EC. By unraveling the distinct effects of different mutations, our study contributes to the identification of personalized treatment strategies for patients with <i>FGFR2</i>-mutated cancers. This knowledge has the potential to guide the development of targeted therapies that specifically address the underlying molecular alterations associated with <i>FGFR2</i> mutations, ultimately improving patient outcomes in EC and potentially other cancer types characterized by <i>FGFR2</i> mutations.