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

Abstract

4p16.3 has previously been identi®ed 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¯uorescent 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 identi®ed 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, 686 ± 691.

Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

“…The identification of mutations in bladder cancers identical (K650/652Q) 18 or similar (K650/652T) (this study) to mutations found in hypochondroplasia suggests that other hypochondroplasia mutations, such as the I538/540V and N540/542K,T,S,V mutations in exon 13 may also occur in this carcinoma. 6,24 In other words, possible hypochondroplasia mutations in other exons than 15 may have escaped their detection in bladder cancer.…”

“…7,9 In the previous published series, only two FGFR3 mutations (A391/393E and K650/ 652Q) did not correspond to thanatophoric dysplasia mutations. 17,18 However, both mutations have been found to be associated with milder types of skeletal dysplasia: the A391/ 393E mutation with the Crouzon syndrome with acanthosis nigricans and the K650/652Q mutation with hypochondroplasia. In this new series of 297 bladder carcinomas reported here, we identified 181 FGFR3 mutations.…”

“…5 **This region containing mutations associated with hypochondroplasia was only examined in 89 of the 570 bladder tumours studied so far. 5,18 FGFR3 mutations in cancer and skeletal disorders BWG van Rhijn et al 822 achondroplasia with developmental delay and acanthosis nigricans) 23 and in a primary multiple myeloma. 12 Transient transfection studies have demonstrated that the K650/ 652M mutation results in stronger constitutive activation of FGFR3 than does the K650/652E mutation responsible for thanatophoric dysplasia.…”

“…5,16 -18 Only two of the 117 FGFR3 mutations identified by these groups, the A393E and K652Q mutations, do not correspond to thanatophoric dysplasia mutations. 17,18 The A393E mutation is identical to a mutation associated with a craniosynostosis syndrome (Crouzon syndrome with acanthosis nigricans) and the K652Q mutation is identical to a mutation associated with hypochondroplasia. 11,19 In this report, we describe three new somatic FGFR3 mutations in bladder tumours (G380/382R, K650/652M and K650/652T) (FGFR3c isoform numbering/FGFR3b isoform numbering).…”

Genetic alterations in urothelial bladder carcinoma

“…These mutations are found in the immunoglobulin (Ig)-like loop domain, the transmembrane domain, and the tyrosine kinase domain, with the most common mutation on the Iglike loop domain: the S249C that occurs in up to 70% of tumors. 71 Because mutations of this gene are seen rarely in other solid tumors, with the exception of a small number of cervical carcinomas, it has been suggested that FGFR3 mutations are specific for UC and reportedly occur in Ͼ 40% of patients with UC. 72,73 Because it is believed that mutations of FGFR3 are very early events in bladder carcinogenesis, their detection in urine may be informative for diagnosing low-grade carcinomas with high sensitivity and specificity.…”