Mutations in FGFR3 and PIK3CA, singly or combined with RAS and AKT1, are associated with AKT but not with MAPK pathway activation in urothelial bladder cancer

Juanpere, Núria; Agell, Laia; Lorenzo, Marta; Muga, Silvia de; López‐Vilaró, Laura; Murillo, Raquel; Mojal, Sergi; Serrano, Sergio; Lorente, José A.; Lloreta, Josep; Hernández, Sílvia

doi:10.1016/j.humpath.2011.10.026

Cited by 58 publications

(47 citation statements)

References 31 publications

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“…This finding is in agreement with previous results on colorectal cancer, bladder cancer, and pancreas neoplasms (36)(37)(38). There was no perfect correlation between PIK3CA mutation and p-AKT, in part because there were other mechanisms of AKT activation (i.e., PTEN loss and/or methylation, PIK3CA amplification, and PIK3RI mutation).…”

Section: Discussionsupporting

confidence: 92%

PIK3CA Mutation Is Associated with a Favorable Prognosis among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma

Shigaki

Baba

Watanabe

et al. 2013

Clinical Cancer Research

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Purpose: PIK3CA encodes the catalytic subunit of PI3K, p110a. Mutant PIK3CA stimulates the AKT pathway and promotes cancer cell proliferation. PIK3CA mutations have been associated with poor prognosis in patients with colorectal or lung cancer. In contrast, the relationship between PIK3CA mutations and favorable prognoses has been shown in breast cancer. However, the influence of PIK3CA mutations on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains unclear.Experimental Design: Using a nonbiased database of 219 curatively resected ESCCs and eight esophageal cancer cell lines, we evaluated PIK3CA mutational status by pyrosequencing. The expression of p53 and phosphorylated AKT (i.e., AKT activation) was evaluated by immunohistochemistry.Results: PIK3CA mutations in exon 9 and/or 20 were detected in 46 cases (21%). No ESCC cell line harbored PIK3CA mutations. PIK3CA mutations were significantly associated with phosphorylated AKT expression, but not with p53 expression, sex, age at surgery, tobacco use, alcohol use, or histologic grade. Compared with wild-type PIK3CA cases, patients with PIK3CA mutations in exons 9 and/or 20 experienced significantly better disease-free survival [log-rank P ¼ 0.0089; univariate HR: 0.37, 95% confidence interval (CI): 0.15-0.75, P ¼ 0.0042; multivariate HR: 0.34, 95% CI: 0.10-0.86, P ¼ 0.021] and overall survival (log-rank P ¼ 0.012; univariate HR: 0.38, 95% CI: 0.16-0.78, P ¼ 0.0060; multivariate HR: 0.35, 95% CI: 0.10-0.90, P ¼ 0.028).Conclusion: PIK3CA mutations in ESCC are associated with longer survival, suggesting its role as a prognostic biomarker. Future studies are needed to confirm this association and to elucidate the exact mechanisms by which PIK3CA mutations affect tumor behavior.

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Section: Discussionsupporting

confidence: 92%

PIK3CA Mutation Is Associated with a Favorable Prognosis among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma

Shigaki

Baba

Watanabe

et al. 2013

Clinical Cancer Research

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“…Co-occurrence of FGFR3 and PIK3CA mutations is reported in the literature (15,40) and found significant in the CIT and Lindgren datasets. As CyclinD1, PI3K is downstream of FGFR3 (Fig.…”

Section: Data Interpretation Using the Modelmentioning

confidence: 83%

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

et al. 2015

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Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer.

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“…Constitutive (ligand-independent) receptor activation occurs most commonly by substitution of a wild-type residue within the extracellular domain of FGFR3 with a cysteine residue, resulting in dimerization and subsequent stimulation of tyrosine kinase activity (11,27). This in turn induces a number of different oncogenic signaling pathways, including the RAS/MAPK, PLCc1, PI3K and STAT pathways (7,17,18). FGFR3 point mutations are found almost exclusively in exons 7, 10 and 15 (19).…”

Section: Discussionmentioning

confidence: 99%

“…FGFR3 belongs to a family of structurally associated tyrosine kinase receptors that are involved in numerous aspects of embryogenesis and tissue homeostasis, as well as being implicated in the tumorigenesis of bladder and other urothelial types of cancer, multiple myeloma and cervical cancer (13)(14)(15). Mutated FGFR3 is constitutively activated and induces a number of oncogenic signaling pathways, including the RAS/mitogen activated protein kinases (MAPK), phospholipase Cc1 (PLCc1), phosphoinositide 3-kinase (PI3K) and signal transducer and activator of transcription (STAT) signaling pathways (11,(16)(17)(18). Activating mutations in FGFR3 genes are associated with genetically stable Ta and low-grade BC, which represent the favorable BC pathway (19).…”

Section: Introductionmentioning

confidence: 99%

Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

et al. 2017

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Abstract. The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, and the prognostic value of FGFR3 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression test. FGFR3 mutations were identified in 48/120 (40.0%) patients with pT1 BC. FGFR3 mRNA expression level was significantly higher in those with BC harboring FGFR3 mutations (P<0.001). Low FGFR3 expression level was associated with high-grade tumors and cancer progression (P=0.006 and P=0.001), whereas FGFR3 mutation status was not associated with cancer progression. Kaplan-Meier analysis revealed a similar result (log-rank, P<0.001). Multivariate analysis identified low FGFR3 expression level (odds ratio, 3.300; 95% confidence interval, 1.310-8.313; P=0.011) as an independent predictor of cancer progression. Stratification by exon site of FGFR3 mutations yielded significant differences in mRNA expression level. None of the patients with BC harboring FGFR3 mutations in exon 9 demonstrated disease progression. The mRNA expression level of the FGFR3 gene may be used to precisely identify subsets of patients with pT1 BC that have a relatively better prognosis. The prognostic influences of FGFR3 mutations may be modulated by the exon site of FGFR3 mutations.

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Mutations in FGFR3 and PIK3CA, singly or combined with RAS and AKT1, are associated with AKT but not with MAPK pathway activation in urothelial bladder cancer

Cited by 58 publications

References 31 publications

PIK3CA Mutation Is Associated with a Favorable Prognosis among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma

PIK3CA Mutation Is Associated with a Favorable Prognosis among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

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