title: 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 five medulloblastoma cell lines for PTCH mutations using an exon-by-exon single strand conformation polymorphism assay. We found three missense mutations, which affect 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 loci flanking PTCH. The finding of LOH at 9q22-q23 in most mutated tumours while present in only three out of 26 tumours, in which a mutation was not identified, implicates PTCH as the target gene in PNETs with LOH at 9q22-q23 and deficient 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 first symptom of NBCCS is likely to be a very uncommon event.
authors.affiliation: Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Vorechovský
authors.forename: O
authors.initials: O
authors.lastname: Tingby
authors.forename: M
authors.initials: M
authors.lastname: Hartman
authors.forename: B
authors.initials: B
authors.lastname: Strömberg
authors.forename: M
authors.initials: M
authors.lastname: Nister
authors.forename: V P
authors.initials: VP
authors.lastname: Collins
authors.forename: R
authors.initials: R
authors.lastname: Toftgård
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001478:Basal Cell Nevus Syndrome / Q000235:genetics; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D002460:Cell Line; D002528:Cerebellar Neoplasms / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D004273:DNA, Neoplasm / Q000235:genetics; D029721:Drosophila Proteins; D005091:Exons; D005260:Female; D005819:Genetic Markers; D053823:Hedgehog Proteins; D006801:Humans; D007223:Infant; D019476:Insect Proteins / Q000235:genetics*; D008297:Male; D008527:Medulloblastoma / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D017384:Sequence Deletion; D015534:Trans-Activators; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D029721:Drosophila Proteins; D005819:Genetic Markers; D053823:Hedgehog Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; C070844:ptc protein, Drosophila