PTCH gene mutations in invasive transitional cell carcinoma of the bladder

Abstract

LOH analysis suggests that multiple tumor suppressor genes play a role in the development of human TCC. The human homolog of the Drosophila PTCH was recently cloned and mapped to the BCNS locus on 9q22.3, a chromosomal region commonly deleted in TCCs. We ®rst examined the steady state mRNA transcription of the PTCH, SMOH and GLI3 genes of the HH signal transduction pathway in TCC cell lines and normal urothelium. Normal urothelium and TCC cell lines express these three genes within the PTCH signal transduction pathway. We then screened for PTCH mutations in`hot spot' exons 6, 8, 13 and 16 by PCR/ SSCP analysis of genomic DNAs from 54 TCC tumor samples and control autologous peripheral blood lymphocytes. DNA sequence analysis con®rmed TCCspeci®c mutations in two of 54 patients (3.7%). These mutations resulted a single amino acid substitution and two frame shifts. One tumor had PTCH mutations in exon 16 as well as exon 13 and one tumor had a mutation in exon 13 alone. Both TCC tumors that contained PTCH mutations had a loss of heterozygosity at 9q. Although the PTCH protein has an unknown function in urothelial cells, the detection of the PTCH, SMOH and GLI3 transcripts in normal urothelium and TCC cell lines and rare PTCH mutations in tumor samples suggest that the HH pathway may have a role in controlling the proliferation of urothelial cells and that PTCH mutations may contribute to the development of a subset of TCCs.

The hedgehog signalling pathway in tumorigenesis and development

“…Other tumours which carry PTCH mutations include the benign skin lesions tricoepitheliomas (TEs), esophageal squamous cell carcinomas and transitional cell carcinomas of the bladder (Vorechovsky et al, 1997b;Maesawa et al, 1998;McGarvey et al, 1998). In addition, although mutations in PTCH are yet to be demonstrated in rhabdomyosarcomas, mice heterozygous for a null allele of patched develop this soft tissue tumour of the muscle at a high frequency (Hahn et al, 1998).…”

Alternative first exons of PTCH1 are differentially regulated in vivo and may confer different functions to the PTCH1 protein

“…The human homologue was originally discovered as the gene responsible for the development of the Nevoid Basal Cell Carcinoma Syndrome (NBCCS), an autosomal dominant developmental disorder characterized by multiple abnormalities and predisposition to development of basal cell carcinomas and other tumours (Hahn et al, 1996a;Johnson et al, 1996). It was shown later that the PTCH1 gene was also mutated in at least 30% of sporadic basal cell carcinomas (Gailani et al, 1996) as well as in several other types of tumours (McGavrey et al, 1998;Vorechovsky et al, 1997a,b). Interestingly, when PTCH1 mRNA levels were examined in BCCs, all the tumours showed upregulation of PTCH1 message (Gailani et al, 1996;Unden et al, 1997).…”

DHPLC Analysis of patients with Nevoid Basal Cell Carcinoma Syndrome reveals novelPTCHmissense mutations in the sterol-sensing domain

“…Inactivation of PTCH has been shown to be a major factor in basal cell carcinoma (BCC) formation (Aszterbaum et al, 1998;Gailani et al, 1996;Unden et al, 1996;Wolter et al, 1997). In addition to BCCs, PTCH has also been implicated in the aetiology of a range of other tumors including medulloblastoma (Pietsch et al, 1997;Wolter et al, 1997), squamous cell carcinomas of the oesophagus (Maesawa et al, 1998), transitional cell carcinomas of the bladder (McGarvey et al, 1998) and the benign skin lesions trichoepitheliomas (Vorechovsky et al, 1997).…”