Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma.
4p16.3 has previously been identified as a region of non-random LOH in transitional 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 dominant skeletal dysplasias, the severity of which depends on the position and nature of the mutation in the protein. We investigated the frequency and nature of FGFR3 mutations in a panel of transitional cell carcinomas and cell lines and studied the possible link between mutation and loss of heterozygosity (LOH) on 4p16.3. FGFR3 coding sequence from 63 transitional cell carcinomas (TCC) of various stages and grades, and 18 cell lines was analysed by fluorescent SSCP. Samples with abnormal migration patterns were sequenced 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 tumours (41%) and 4/18 (22%) of the cell lines had missense mutations in FGFR3. All mutations detected in our panel have been reported in the germline where all apart from one cause lethal conditions. One tumour contained K652Q which has recently been identified in less severe cases of skeletal dysplasia. Tumours with and without LOH at 4p16.3 had mutations in FGFR3 suggesting that these two events are not causally linked. The frequency of FGFR3 mutation indicates that this protein plays an important role in TCC.
Sibley
K
K
ICRF Clinical Centre, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Cuthbert-Heavens
D
D
Knowles
M A
MA
D002295:Carcinoma, Transitional Cell / Q000145:classification / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004273:DNA, Neoplasm; D006801:Humans; D019656:Loss of Heterozygosity; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D001749:Urinary Bladder Neoplasms / Q000145:classification / Q000235:genetics*
D004273:DNA, Neoplasm; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3