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Mutations in multiple oncogenes including  KRAS ,  CTNNB1 ,  PIK3CA  and  FGFR2  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  FGFR2 ,  KRAS ,  CTNNB1 , and  PIK3CA . 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  FGFR2  (48/466);  KRAS  (87/464);  CTNNB1  (88/454) and  PIK3CA  (104/464).  KRAS  and  FGFR2  mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors.  KRAS  and  FGFR2  occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in  KRAS  and  CTNNB1  also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in  KRAS  and  FGFR2  showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II),  FGFR2  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  KRAS  was associated with longer DFS (HR = 0.23; 95% CI 0.05–0.97; p = 0.045). In conclusion, although  KRAS  and  FGFR2  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.

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