Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors

Abstract

We recently identified activating mutations of fibroblast growth factor receptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the incidence of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma in situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. All 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dysplasia, a lethal form of dwarfism. The S249C mutation, found in 33 of the 48 mutated tumors, was the most common. The frequency of mutations was higher in pTa tumors (37 of 50, 74%) than in CIS (0 of 20, 0%; P < 0.0001), pT1 (4 of 19, 21%; P < 0.0001) and pT2-4 tumors (7 of 43, 16%; P < 0.0001). Bladder cancer is the fourth most common malignancy in men and the ninth most common in women in the Western world. In these countries, more than 90% of bladder tumors are urothelial carcinomas. At the time of initial diagnosis, approximately 80% of urothelial carcinomas are confined to the epithelium (pTa, CIS) or lamina propria (pT1), whereas the remaining 20% invade the muscularis propria (pT2, pT3, pT4). pTa lesions, the most common form of bladder carcinoma, are papillary tumors. Carcinoma in situ (CIS) are flat, cytologically highgrade carcinomas. Primary isolated CIS is a very rare entity, CIS being more commonly associated with other malignant bladder lesions. 1 Clinical evidence and molecular studies suggest that there are two pathways in bladder carcinogenesis responsible for generating two types of urothelium-confined tumors (pTa and CIS) with very different behavior. 1-6 pTa tumors are associated with a high rate of recurrence (50 -75%) but a low probability (Ͻ5%) of progression to lamina propria-invasive (pT1) and muscleinvasive (pT2-4) tumors. CIS may be the most common precursor of invasive bladder cancer because CIS shows a strong tendency to progress (40 -50%), and because most muscle-invasive lesions arise with no history of a pTa precursor lesion. This clinical evidence is supported by various molecular studies showing that CIS and invasive tumors have many genetic alterations in common, such as specific chromosomal deletions and a high frequency of p53 mutations. 2,7 In our search for new markers of carcinoma progression, we recently reported specific missense mutations in a gene encoding a growth factor receptor, fibroblast

FGFR3 mutations in prostate cancer: association with low-grade tumors

“…Mutations in this gene have been reported in bladder and cervix carcinoma, multiple myeloma, colon cancer and, more recently, in benign skin tumors. [25][26][27][28][29][30][31][32][33] The relatively high prevalence of FGFR3 mutations in benign skin tumors and in noninvasive bladder tumors suggests an association of FGFR3 mutation with low risk cancers. 35,41 Although it seems that anomalous FGF signaling is involved in prostate carcinogenesis, the functional role of FGFR3 and its alterations in prostate cancer are unknown.…”

“…It is well known that FGFR3 mutations are frequent in superficial tumors but not in muscle-invasive tumors. [27][28][29]35 Thus, another possible explanation for the discrepant mutational status of FGFR3 in the bladder and prostate tumors could be that the bladder tumor had lost the mutated FGFR3 allele along its progression.…”

“…[22][23][24] FGFR3 mutations identical to those found in these disorders have been reported in multiple myelomas, cervix and bladder cancer, colon cancer, and benign skin tumors. [25][26][27][28][29][30][31][32][33] This gene constitutes a promising marker in the clinical management of patients with low-grade, non-muscle-invasive bladder tumors. 29 However, very few authors have analyzed the mutational status of the FGFR3 gene in prostate tumors.…”

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

“…Mutations of FGFR3 are strongly associated with a low tumour grade and stage, with up to 60 -70% of low-grade pTa tumours showing these mutations (Billerey et al, 2001;van Rhijn et al, 2001;Jebar et al, 2005). Therefore, in addition to chromosomal alterations, FGFR3 mutations are used as a clonal marker.…”

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells

“…Typically, the predicted transcription products exhibit a frame-shift and premature termination in exon 10, so no functional protein product is translated (Jang et al, 2000). Where mutations of FGFR3 are frequent events, forexample, in bladder cancer (Cappellen et al, 1999;Billerey et al, 2001;van Rhijn et al, 2001;Sibley et al, 2001), nonsense mutations inserted within its coding region may result in altered splice site selection (Valentine, 1998). This is unlikely to be the case for the majority of cancers where mutations of FGFR3 are rare (Intini et al, 2001;Karoui et al, 2001;Sibley et al, 2001), although FGFR3 may be inactivated by aberrant-splicing and activation of cryptic splice donor sites (Jang et al, 2000).…”