Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma

We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer

Patient Demographics and Clinicopathologic Characteristics.

<p>Patient Demographics and Clinicopathologic Characteristics.</p

Potential utility of <i>FGFR2</i> mutation status as an adverse prognostic factor to affect clinical decision-making.

<p>The decision tree is adapted from 2011 National Comprehensive Cancer Network guidelines using FIGO 2009 staging. BT = brachytherapy; RT = radiation therapy.</p

Schematic figure of FGFR2 mutations identified in endometrioid endometrial tumors.

<p>Blue diamonds indicate each instance of a mutation in the Washington University School of Medicine cohort. Mutations are numbered relative to <i>FGFR2</i>b (NP_075259.2). Mutations at 6 codons (S252, P253, Y376, C383, N550, K660) comprise >90% of all mutations identified.</p

Hazard ratio (HR) and 95% confidence interval (CI) for cohort of 386 Stage I/II cases.

<p>*For DFS, the multivariate model included Stage 1C, II, Grade 2 and 3.</p><p>**For OS, the multivariate model included age, FIGO Stage 1C, II, Grade 2 and Grade 3.</p>a<p>FGFR2 adjusted for KRAS in addition to covariates above.</p>b<p>KRAS adjusted for FGFR2 in addition to covariates above.</p

Hazard Ratio (HR) and 95% Confidence Interval (CI) for Cohort of 466 Endometrioid Endometrial Cancers.

<p>*For DFS, the multivariate model included Stage 1C, II, III/IV, grade 2 and 3.</p><p>**For OS, the multivariate model included age, FIGO stage 1C, II, III/IV, grade 2 and grade 3.</p>a<p>FGFR2 adjusted for KRAS in addition to covariates above.</p>b<p>KRAS adjusted for FGFR2 in addition to covariates above.</p

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

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