<em>FGFR2</em> Point Mutations in 466 Endometrioid Endometrial Tumors: Relationship with MSI, <em>KRAS</em>, <em>PIK3CA</em>, <em>CTNNB1</em> Mutations and Clinicopathological Features

<div><p>Mutations in multiple oncogenes including <em>KRAS</em>, <em>CTNNB1</em>, <em>PIK3CA</em> and <em>FGFR2</em> have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in <em>FGFR2</em>, <em>KRAS</em>, <em>CTNNB1</em>, and <em>PIK3CA</em>. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in <em>FGFR2</em> (48/466); <em>KRAS</em> (87/464); <em>CTNNB1</em> (88/454) and <em>PIK3CA</em> (104/464). <em>KRAS</em> and <em>FGFR2</em> mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. <em>KRAS</em> and <em>FGFR2</em> occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in <em>KRAS</em> and <em>CTNNB1</em> also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in <em>KRAS</em> and <em>FGFR2</em> showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), <em>FGFR2</em> mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35–7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09–3.65; p = 0.025) and <em>KRAS</em> was associated with longer DFS (HR = 0.23; 95% CI 0.05–0.97; p = 0.045). In conclusion, although <em>KRAS</em> and <em>FGFR2</em> mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.</p>