Alteration of the PATCHED locus in superficial bladder cancer

Chromosome 9 alterations are the most frequently encountered cytologic anomalies in urothelial carcinoma (UC). We previously screened 139 low-stage UCs for loss of heterozygosity on chromosome 9, and identified five distinct regions likely to harbour tumour-suppressor genes. The present study focused on deletion mapping in the 9q22 region with 11 additional microsatellite markers. New deletions in the 9q22 region were found in five tumours. Deletion mapping allowed us to identify a 0.5 CM common minimal region of deletion between markers D9S280 and D9S1809, encompassing PATCHED (PTC), a gene identified as a tumour suppressor in basal cell carcinoma and in medulloblastoma. A marker located in the first intron of this gene showed the highest percentage of deletion (45%). cDNA sequencing in 15 tumours with deletion of PTC showed no mutation in the remaining allele. However, average expression of PTC mRNA measured by semiquantitative RT-PCR was significantly decreased in tumours with LOH in the 9q22 region, compared to normal urothelium (P=0.04), while it showed marked fluctuations in tumours without deletion. Our results suggest that the PTC gene is a putative suppressor at the 9q22 locus and that haploinsufficiency of this gene may be an early event in the development of papillary bladder tumours.