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

• Published in: Oncogene Vol. 15; no. 3; pp. 361 - 366
• Main Authors: VORECHOVSKY, I, TINGBY, O, HARTMAN, M, STRÖMBERG, B, NISTER, M, COLLINS, V. P, TOFTGARD, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 17.07.1997; Nature Publishing Group
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Basal cell carcinoma; Basal Cell Nevus Syndrome - genetics; Base Sequence; Biological and medical sciences; Brain Neoplasms - genetics; Carcinoma; Cell Line; Cerebellar Neoplasms - genetics; Child; Child, Preschool; Children; Chromosome Mapping; Chromosomes, Human, Pair 9; Conformation; DNA, Neoplasm - genetics; Drosophila Proteins; Exon skipping; Exons; Female; Gene deletion; Genetic Markers; Hedgehog Proteins; Hereditary diseases; Heterozygosity; Humans; Infant; Insect Proteins - genetics; Loss of heterozygosity; Male; Medical sciences; Medicin och hälsovetenskap; Medulloblastoma; Medulloblastoma - genetics; Membrane Proteins - genetics; Missense mutation; Molecular Sequence Data; Mutation; Nervous system diseases; Neuroectodermal Tumors, Primitive - genetics; Neurology; Patched protein; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Proteins - metabolism; Receptors, Cell Surface; Sequence Deletion; Skin cancer; Trans-Activators; Transmembrane domains; Tumor Cells, Cultured; Tumors; Tumors of the nervous system. Phacomatoses; Genetic mapping; Human; Skin disease; Nervous system diseases; Neurospongioma; Heterozygosity loss; Carcinogenesis; Chromosome C9; Genetic disease; Neuroectodermal tumor; Somatic mutation; Cell line; Basal cell nevus syndrome; Child
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201340

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.