Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors

We recently identified activating mutations of fibroblast growth factor rec eptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the inciden ce of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma i n situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. Ah 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dy splasia, 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 high er 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), FG FR3 mutations were detected in 27 of 32 (84%) G1, 16 of 29 (55%) G2, and 5 of 71 (7%) G3 tumors. This association between FGFR3 mutations and low grad e was highly significant(P < 0.0001)FGFR3 is the first gene found to be mut ated at a high frequency in pTa tumors. The absence of FGFR3 mutations in C IS and the low frequency of FGFR3 mutations in pT1 and pT2-4 tumors are con sistent with the model of bladder tumor progression in which the most commo n precursor of pT1 and pT2-4 tumors is CIS.