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. 2012;7(2):e30801.
doi: 10.1371/journal.pone.0030801. Epub 2012 Feb 23.

FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features

Sara A Byron  1 , Michael Gartside, Matthew A Powell, Candice L Wellens, Feng Gao, David G Mutch, Paul J Goodfellow, Pamela M Pollock
Affiliations

FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features

Sara A Byron et al. PLoS One. 2012.

Erratum in

  • PLoS One. 2012;7(2):doi/10.1371/annotation/0bfaecca-0f87-43fe-97cc-f2ae3ddeb6d5

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.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts to declare: Matthew Powell - Honoraria from Speakers Bureau (Merck, Sanofi-Aventis, OrthoBiotech) and Consultant/Advisory Board (Eisai, Glaxo-Smith-Klein, Novartis, OrthoBiotech, Sanofi-Aventis, Genetech). Dr. Pollock and Dr. Goodfellow have filed two patents regarding the detection of FGFR2 mutations in endometrial cancer samples (20100111944, Method of Diagnosing, Classifying and Treating Endometrial Cancer and Precancer, filed 24 March 2008) as well as a second patent regarding utilizing FGFR2 mutations to predict increased risk of recurrence in endometrial cancer patients (WO2011009114, Method of assessing Endometrial Cancer risk, Filed July 2009) which is relevant to this manuscript. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Schematic figure of FGFR2 mutations identified in endometrioid endometrial tumors.
Blue diamonds indicate each instance of a mutation in the Washington University School of Medicine cohort. Mutations are numbered relative to FGFR2b (NP_075259.2). Mutations at 6 codons (S252, P253, Y376, C383, N550, K660) comprise >90% of all mutations identified.
Figure 2
Figure 2. Pattern of KRAS, CTNNB1, FGFR2, PIK3CA mutations and MSI status in 466 endometrioid endometrial tumors.
Gene mutations and MSI positive status are depicted by colored bars. 258 tumors had a mutation in at least one of the genes evaluated, whereas 208 tumors did not demonstrate mutation of KRAS, CTNNB1, FGFR2, or PIK3CA.
Figure 3
Figure 3. Potential utility of FGFR2 mutation status as an adverse prognostic factor to affect clinical decision-making.
The decision tree is adapted from 2011 National Comprehensive Cancer Network guidelines using FIGO 2009 staging. BT = brachytherapy; RT = radiation therapy.
See this image and copyright information in PMC

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