FGFR3 and P53 Characterize Alternative Genetic Pathways in the Pathogenesis of Urothelial Cell Carcinoma

Abstract

Fibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53 overexpression in 25%. Interestingly, FGFR3 and P53 alterations were mutually exclusive, because they coincided in only 5.7% of tumors. Consequently, we propose that they characterize two alternative genetic pathways in urothelial cell carcinoma pathogenesis. The genetic alterations were reflected in the pathology and the clinical outcome, i.e., FGFR3 mutations were found in low-stage/-grade tumors and were associated with a favorable disease course, whereas P53 alterations were tied to adverse disease parameters.

Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis

“…Furthermore, our results did not directly indicate that either the FGFR4 genotype or TP53 mutation status was an independent predictor of prognosis for bladder cancer but that they might act jointly on the disease-specific survival of patients, which supports the hypothesis that the FGFR3 and TP53 gene mutations may represent two alternative genetic pathways in the progression of bladder cancer (van Rhijn et al, 2004). A trend showed a better disease-specific survival rate for bladder cancer patients with the Arg/Arg genotype.…”

“…Mutations in the FGFR3 and TP53 genes are the two most frequent events observed in primary bladder tumours and have occurred in 59% and 25% of tumours, respectively (van Rhijn et al, 2004). TP53 mutations are often found in advanced tumours and, thus, are associated with a poor prognosis.…”

Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma

“…In addition, gene expression analysis disclosed overexpression of FGF3 in a high proportion of the analyzed cases (8 of 12). The oncogenic activation of FGFR3, which activates MAPK pathway, has been reported at much higher frequency (30-70%) in low-grade noninvasive papillary tumors than in high-grade invasive cancer (10-20%) 7,8,33,34 and the presence of FGFR3 mutations to correlate with genetically stable tumors. 35 Novel candidate oncogenes were also discovered, such as MYBL2, a nuclear protein involved in cell cycle progression; YWHAB, an antiapoptotic protein of the 14-3-3-family; and SDC4, an important component of focal adhesions, which represent interesting candidates detected within 2 independent amplicons on chromosome 20, for which DNA amplification was linked to transcript up-regulation.…”

“…Activating mutations in fibroblast growth factor receptor-3 (FGFR3), a tyrosine kinase receptor that leads to the stimulation of MAPK pathway, characterizes low-risk tumors and has been reported at much higher frequency (30-70%) in low-grade noninvasive papillary tumors than in high-grade invasive tumors (10-20%). 7,8 However, reported chromosomal imbalances in Ta low-grade papillary tumors are few, and the most common are 9q and 9p deletions, which are present in $40% of the tumors in this category. 9 Four different minimal tumor suppressor candidate regions have been mapped to this chromosome, 9p21, 9q22, 9q32-33 and 9q34, 10,11 encompassing the tumor suppressor genes cyclin-dependent kinase inhibitor-2A (CDKN2A) and cyclin-dependent kinase inhibitor-2B (CDKN2B), patched homolog-1 (PTCH1; Drosophila), 12,13 deleted in bladder cancer-1(DBC1) 14,15 and tumor suppressor candidate-1 (TSC1).…”

Genetic alterations in urothelial bladder carcinoma

“…101 One pathway is through mutation activation of FGFR3, in which the tumors are low-grade/stage, and patients have favorable outcomes. The other pathway is through p53 mutations, and those tumors are invasive and aggressive.…”