Molecular Genetics of Urological Cancer

Previous and current research
We are interested in the genetics of urological cancers, particularly the identification of genes whose mutation may occur early in bladder tumour development. Chromo-some 9 deletions are present in more than 60% of bladder tumours. Several tumour suppressor genes are implicated including CDKN2A/p14ARF on 9p and three loci mapped on 9q. We have identified candidates for two of the 9q loci. One of these, DBCCR1 at 9q32-33 shows promoter methylation in bladder tumours and cell lines. The second is the tuberous sclerosis gene TSC1 at 9q34, which is mutated in some bladder tumours. At present both of these candidate bladder suppressor genes are the subject of mutational and functional analyses. We are also identifying candidate genes within a commonly deleted region on 4p and mapping a critical region of 8p, deletion of which shows strong association with muscle invasion.

Future projects
Future studies will include the development of appropriate in vitro and animal models to explore the function of genes implicated in the development of urothelial cancer. At diagnosis most bladder tumours are low grade papillary lesions in which no common genetic changes apart from deletions of chromosome 9 and mutation of FGFR3 have been found. We are now using array CGH as an approach to identify other heritable changes in such tumours that may be used as molecular markers or targets for therapy. Bladder cancer is often a multifocal disease, the natural history of which is poorly understood. We aim to clarify this by a detailed examination of the timing of genetic changes during tumour development and of the genetic relationships of tumours and preneoplastic lesions in the same bladder.