Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma

4p16,3 has previously been identified as a region of nonrandom LOH in trans itional cell carcinoma, suggesting the presence of a tumour suppressor gene . One candidate within this region is fibroblast growth factor receptor 3 ( FGFR3). Germline mutations in FGFR3 are known to cause several autosomal do minant skeletal dysplasias, the severity of which depends on the position a nd nature of the mutation in the protein. We investigated the frequency and nature of FGFR3 mutations in a panel of transitional cell carcinomas and c ell lines and studied the possible link between mutation and loss of hetero zygosity (LOH) on 4p16.3. FGFR3 coding sequence from 63 transitional cell c arcinomas (TCC) of various stages and grades, and 18 cell lines,vas analyse d by fluorescent SSCP, Samples with abnormal migration patterns were sequen ced to identify the mutation or polymorphism. Thirty-one of the 63 tumours had previously been assessed to have LOH at 4p16,3, Twenty -six of the 63 t umours (41%) and 4/18 (22%) of the cell lines had missense mutations in FGF R3. All mutations detected in our panel have been reported in the germline where all apart from one cause lethal conditions. One tumour contained K652 Q which has recently been identified in less severe cases of skeletal dyspl asia. Tumours with and without LOH at 4p16,3 had mutations in FGFR3 suggest ing that these tno events are not causally linked. The frequency of FGFR3 m utation indicates that this protein plays an important role in TCC.