Alteration of the PATCHED locus in superficial bladder cancer

Abstract

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 ¼ 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.

Accelerated Induction of Bladder Cancer in Patched Heterozygous Mutant Mice

“…A marker within this gene was deleted in 46% of tumors. Moreover, semiquantitative reverse transcription-PCR mRNA expression analysis showed a significant decrease in the expression of PTC in tumors with loss of heterozygosity of the PTC marker (3). We also observed a significantly increased tumor recurrence rate in patients with tumors having loss of heterozygosity at the 9q22 locus (4).…”

“…In an attempt to identify candidate chromosome 9 TSGs, we conducted a mapping of losses of heterozygosity of microsatellite markers in initial superficial papillary bladder tumors (Ta/T1; Refs. 2,3). This mapping led us to define a 0,5 cM minimal region of deletion at 9q22.3 encompassing the PATCHED (PTC) gene.…”

A mouse prostate cancer model induced by Hedgehog overexpression

“…Abnormal Shh hyperactivation was found in small-cell lung cancer [12], pancreatic cancer [13], digestive tract tumors [14], and ameloblastomas [15]. Mutations in Ptc gene, a tumor suppressor gene and a Shh signaling pathway repressor, was shown to cause cerebellar medulloblastomas [16] and basal cell carcinomas [17] in mice, and was implicated in human superficial bladder cancer [18]. In concordance with the observations in other tumors, several lines of evidences have indicated Hedgehog signaling in prostate tumorigenesis.…”

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

“…Two microsatellite markers were studied: (i) a CGG repeat localised in the 5 0 UTR, which was genotyped by sequencing PTCH exon 1, and (ii) a CA repeat localised in intron 2 (Aboulkassim et al, 2003), which was genotyped by migration of the fluorescent- labelled PCR product on a 310 Genetic Analyzer (Applied Biosystems).…”