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

Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, Goodfellow PJ, Pollock PM - PLoS ONE (2012)

Bottom Line: KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

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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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.
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pone-0030801-g002: 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.

Mentions: 158/466 (34%) of tumors were MSI positive. Mutations in KRAS were significantly more common in MSI positive tumors (42/158; 28%) compared to microsatellite stable (MSS) tumors (45/306; 14%) (p = 0.003, Fisher's exact test). Similarly, mutations in FGFR2, were significantly more common in MSI positive tumors (24/158; 15%) compared to MSS tumors (24/308; 8%) (p = 0.016). In contrast, mutations in CTNNB1 were significantly less common in MSI positive tumors (17/152; 11%) compared to MSS tumors (71/302; 24% p = 0.002). Mutations in PIK3CA were more common in MSI positive tumors (43/158; 27%) compared to MSS tumors (61/306; 20%), although this was not significant (p = 0.08). Figure 2 summarizes the patterns of mutations and association with MSI status.


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

Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, Goodfellow PJ, Pollock PM - PLoS ONE (2012)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285611&req=5

pone-0030801-g002: 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.
Mentions: 158/466 (34%) of tumors were MSI positive. Mutations in KRAS were significantly more common in MSI positive tumors (42/158; 28%) compared to microsatellite stable (MSS) tumors (45/306; 14%) (p = 0.003, Fisher's exact test). Similarly, mutations in FGFR2, were significantly more common in MSI positive tumors (24/158; 15%) compared to MSS tumors (24/308; 8%) (p = 0.016). In contrast, mutations in CTNNB1 were significantly less common in MSI positive tumors (17/152; 11%) compared to MSS tumors (71/302; 24% p = 0.002). Mutations in PIK3CA were more common in MSI positive tumors (43/158; 27%) compared to MSS tumors (61/306; 20%), although this was not significant (p = 0.08). Figure 2 summarizes the patterns of mutations and association with MSI status.

Bottom Line: KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

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.

Show MeSH
Related in: MedlinePlus