title: Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion.
abstract: The majority of patients with Von Hippel-Lindau (VHL) disease are affected by a VHL germline mutation involving one copy of the VHL gene. Loss of heterozygosity of the second VHL allele can be consistently demonstrated in tumor tissue from these patients, suggesting that allelic deletion is a very early or even initiating event for tumorigenesis. Approximately 20% of VHL disease patients, however, exhibit germline deletion of one entire copy or at least a substantial part of the VHL gene. To investigate the nature of the "second genetic hit" in this patient population, we analysed two renal cell carcinomas and one CNS hemangioblastoma from three unrelated patients for genetic changes of the second copy of the VHL gene. All three tumors showed retention of one VHL allele by FISH. Single-strand conformation polymorphism and mutation analysis of microdissected tumor DNA revealed somatic point mutations of the wild-type VHL copies in each of the three tumors. The results indicate that the "two hit model" is equally applicable to patients with VHL germline mutation and VHL germline deletion. In contrast to tumors from patients with VHL germline mutation, however, point mutations of the wild-type allele can be detected in tumors from patients with VHL germline deletion.
authors.affiliation: Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Building 10, Room 5D37, Bethesda, MD 20892, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Steve C
authors.initials: SC
authors.lastname: Huang
authors.forename: Svetlana D
authors.initials: SD
authors.lastname: Pack
authors.forename: Christian A
authors.initials: CA
authors.lastname: Koch
authors.forename: Irina A
authors.initials: IA
authors.lastname: Lubensky
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics*; D003062:Codon / Q000235:genetics; D005091:Exons / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D018325:Hemangioblastoma / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics*; D008025:Ligases / Q000235:genetics*; D008957:Models, Genetic; D017354:Point Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D017384:Sequence Deletion / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: D003062:Codon; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human