title: VHL mutation analysis in patients with isolated central nervous system haemangioblastoma.
abstract: Haemangioblastomas of the CNS are a cardinal feature of von Hippel-Lindau (VHL) disease, a dominantly inherited multisystem familial cancer syndrome caused by germline mutation of the VHL tumour suppressor gene. We investigated the frequency of VHL mutations in 188 patients presenting with a single haemangioblastoma, no family history of VHL disease and no evidence of retinal or abdominal manifestations of the disease at the time of diagnosis. We found that approximately 4% of patients had a detectable VHL mutation and all of these cases presented age 40 years or less. Although the identification of a germline VHL mutation has important consequences for the patient (e.g. risk of further CNS and extra-CNS tumours) and their relatives, four patients had germline VHL missense mutations [C162Y, D179N and R200W (two patients)] that may represent haemangioblastoma-only and/or low penetrance mutations. Approximately 5% of patients without a detectable VHL mutation subsequently developed a further 'VHL type tumour' (in most cases a further CNS haemangioblastoma). These findings suggest that a subset of patients with apparently sporadic CNS haemangioblastoma will have a germline VHL mutation but may not be at risk for developing classical VHL disease and a further group may be mosaic for a germline VHL mutation that cannot be detected in blood cells.
authors.affiliation: Cancer Research UK Renal Molecular Oncology Group, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, UK.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
authors.forename: Kerry
authors.initials: K
authors.lastname: Wall
authors.forename: Joan
authors.initials: J
authors.lastname: Forsyth
authors.forename: Fiona
authors.initials: F
authors.lastname: Macdonald
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000150:complications / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics; D018325:Hemangioblastoma / Q000150:complications / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D012307:Risk Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D051794:Von Hippel-Lindau Tumor Suppressor Protein