title: FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features.
abstract: 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.
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Byron
authors.forename: Michael
authors.initials: M
authors.lastname: Gartside
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: Candice L
authors.initials: CL
authors.lastname: Wellens
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
mesh_terms: D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D017354:Point Mutation; D016016:Proportional Hazards Models; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D016896:Treatment Outcome; D051176:beta Catenin / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D018631:ras Proteins