Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours

Abstract

The naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinomas (BCCs). Medulloblastomas, primitive neuroectodermal tumours (PNETs) arising in childhood, occur in about 3 ± 5% of NBCCS patients and a subset of PNETs was previously found with allelic imbalance at 9q22-q23, the region containing the gene for NBCCS (PTCH). We have analysed tumour DNA samples from 37 unrelated patients with sporadic PNETs and ®ve medulloblastoma cell lines for PTCH mutations using an exon-by-exon single strand conformation polymorphism assay. We found three missense mutations, which aect conserved residues in transmembrane domains of the gene product and in the extracellular loop implicated in binding sonic hedgehog, one 2 bp deletion and an exon skipping splice site mutation. Most mutations were associated with the absence of the wild-type allele and were found in tumours exhibiting loss of heterozygosity (LOH) at locī anking PTCH. The ®nding of LOH at 9q22-q23 in most mutated tumours while present in only three out of 26 tumours, in which a mutation was not identi®ed, implicates PTCH as the target gene in PNETs with LOH at 9q22-q23 and de®cient PTCH in the development of a subset of these tumours. Since all observed mutations were absent in the germ-line, a sporadic medulloblastoma developing as the ®rst symptom of NBCCS is likely to be a very uncommon event.

The hedgehog signalling pathway in tumorigenesis and development

“…In keeping with the predisposition of NBCCS patients to developing the childhood brain tumour medulloblastoma, mutations of both PTCH and smoothened have been detected in sporadic medulloblastomas and other primitive neuroectodermal tumours (Pietsch et al, 1997;Ra el et al, 1997;Reifenberger et al, 1998;Vorechovsky et al, 1997a;Wolter et al, 1997). NBCCS patients develop the desmoplastic histological subtype of medulloblastoma, and while one study reported PTCH mutations exclusively in this subtype (Pietsch et al, 1997), mutations in classic medulloblastomas have also been described (Wolter et al, 1997).…”

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…The binding of Hedgehog ligands to the PTCH receptor activates Gli signal transducers that then translocate into the nucleus to activate or repress transcription of its downstream genes. Aberrant Hedgehog signaling has been linked to the development of medulloblastomas, the common childhood tumors (Goodrich et al, 1997;Vorechovský et al, 1997;Shahi et al, 2008). Active Hedgehog-Gli signaling is also associated with gliomas (Shahi et al, 2008).…”

Sonic hedgehogRegulates Proliferation and Inhibits Differentiation of CNS Precursor Cells

“…Loss-of-function mutations in human PATCHED are associated with activation of the Hedgehog signal transduction pathway and promotion of a neoplastic state characterized by proliferating, undifferentiated cell populations (Hahn et al, 1996;Johnson et al, 1996). Of the children with Gorlin's Syndrome, which is caused by inherited mutations of PATCHED, 3-5% develop medulloblastoma (Vorechovsky et al, 1997). Inactivating mutations of PATCHED have also been found in sporadically occurring medulloblastoma (Raffel et al, 1997) and basal cell carcinoma, and mice heterozygous for targeted mutations of Patched, in which Shh targets are potentially upregulated, develop cerebellar tumors (Goodrich et al, 1997).…”