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

Oncogene (2001) 20, 686 691 2001 Nature Publishing Group All rights reserved 0950 9232/01 $15.00www.nature.com/oncLoss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell

carcinomaKathryn Sibley1, Darren Cuthbert-Heavens2 and Margaret A Knowles*,11ICRF Clinical Centre, St James's University Hospital, Leeds, UK; 2ICRF Mutation Detection Facility, St James's University

Hospital, Leeds, UK4p16.3 has previously been identied as a region of nonrandom LOH in transitional cell carcinoma, suggesting

the presence of a tumour suppressor gene. One candidate

within this region is broblast 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 uorescentSSCP. 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 identied 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. Oncogene

(2001) 20, 686691.Keywords: bladder; cancer; FGFR3; mutationIntroductionBladder cancer is the fourth most common cancer in

males in the US and UK (Landis et al., 1999; HMSO,

1994). Tumour development is believed to require

multiple genetic events which result in both the

activation of oncogenes and the inactivation of tumour

suppressor genes. One way to identify tumour

suppressor genes involved in bladder cancer has beenrstly to identify common regions of chromosomal loss

followed by mutation analysis of candidate genes on

the retained allele. LOH of chromosome 4 has been

identied in...