Frequent FGFR3 mutations in urothelial papilloma

Abstract

Activating point mutations in the FGFR3 gene occur frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas. This study investigates the incidence of FGFR3 mutations in 12 urothelial papillomas and 79 pTaG1 tumours which were regraded according to the 1998 WHO/ISUP classification system, resulting in 62 papillary urothelial neoplasms of low malignant potential (PUNs-LMP) and 17 low-grade papillary urothelial carcinomas (LG-PUCs). FGFR3 mutation analysis of 21 ovarian Brenner tumours was also performed. Seventy-seven cases were detected with a mutation in the FGFR3 gene. The mutations were exclusively found in bladder neoplasms. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. This report is the first to describe a genetic defect in urothelial papilloma. A comparable percentage of mutations was found in PUNs-LMP (85%) and LG-PUCs (88%). No mutations were found in matched normal DNA from bladder tumour patients. The mean follow-up was 5.78 years (range 0.21-17.60 years). Five patients developed high-grade papillary urothelial carcinoma from 2.5 to 12 years after first diagnosis. Two patients died of bladder cancer. The mean number of recurrences (recurrence rate) per year was 0.03, 0.21, and 0.46, respectively, for papilloma, PUN-LMP, and LG-PUC. Urothelial papilloma is a rare lesion with a benign natural behaviour compared with PUN-LMP and LG-PUC of the bladder, but from a molecular perspective, papillomas should be classified together with all well-differentiated urothelial neoplasms.

FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations

“…19 Specific codons involved in point mutations in urothelial carcinomas include 248, 249, 372, 375, and 652. 15,20 Tumors harboring more than one FGFR3 mutation have been identified. 10,21 FGFR3b-S249C, the most common mutation in bladder tumors, was found to be tumorigenic in vitro and also gave rise to tumors in mice that were xenografted with FGFR3b-S249C transfected cells.…”

“…Higher-grade tumors are much less likely to harbor FGFR3 mutations; in contrast, they often exhibit TP53 mutations. 20 Low-grade papillary tumors typically harbor activating mutations of FGFR3. These tumors tend to be genetically stable even if they do frequently recur.…”

ALDH1 in Combination with CD44 as Putative Cancer Stem Cell Markers are Correlated with Poor Prognosis in Urothelial Carcinoma of the Urinary Bladder

“…Low-grade (G1, G2) noninvasive papillary (pTa and pT1/pTis) UC account for approximately 70-80% of all bladder cancers which are caused by mutations in the fibroblast growth receptor (FGFR3) gene which causes activation of receptor tyrosine kinase-Ras pathway (Harvey Rasor PI3-kinase) (Billerey et al, 2001;van Rhijn et al, 2002;Wu, 2005;. Compared to low-grade tumors, the FGFR3 mutation was not seen in high-grade (G3) flat-muscle invasive (greater than pT2) cancers which have the oncogenic mutations with loss of p53 and retinoblastoma (RB) tumor-suppressor gene activity (Cordon-Cardo et al, 1997;Cote et al, 1998;Wu, 2005;Brandt et al, 2009;Su et al, 2010).…”

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

“…The mutations in the extracellular domain generating an additional cysteine residue lead to the formation of an intermolecular cysteine disulfide bridge, which results in constitutive receptor dimerization and activation (93). Several mutations of amino acid residue K650 in the kinase domain of FGFR3 are also found in bladder cancer (80,81,92). The mutations K650Q/M/N/E are thought to drive the activation loop of the kinase to an active conformation as well as to disengage the autoinhibitory molecular brake in the kinase domain (15).…”

“…Somatic activating mutations in FGFR3 have been identified in approximately 60% to 70% of nonmuscle-invasive and in 16% to 20% of muscle-invasive bladder cancer, with S249C and Y373C mutations being the most frequent (Table 1; refs. 81,91,92). These mutants represent highly activated forms of the receptor and are also found in the lethal skeletal disorder thanatophoric dysplasia.…”