title: Second hit deletion size in von Hippel-Lindau disease.
abstract: von Hippel-Lindau (VHL) disease is caused by germline mutations of the VHL tumor suppressor gene. Affected individuals are predisposed to development of multiple neoplastic and preneoplastic lesions of different organs. A "second hit," which is usually represented by deletion in the wild-type VHL allele at 3p25, is necessary for initiation of tumor formation. The impact of the size of this deletion is thought to be critical, because other tumor suppressor genes are located nearby, but this has not yet been studied in detail. We mapped the deletion size of the "second hit" in microdissected tissue from 16 different VHL-associated lesions from the same patient using 10 polymorphic chromosome 3 markers. We found that the deletion size is highly variable, ranging from short deletions around the VHL gene to complete loss of the chromosome 3. The deletion sizes are not correlated with the site of the germline mutation, the affected organ, or the type or biological behavior of the tumor. Even preneoplastic cystic structures may harbor entire loss of the chromosome 3, suggesting that loss of VHL gene function alone is not immediately causative for neoplastic growth, but further events, either mutations and deletions in other chromosomes or epigenetic or other than genetic phenomena, are required for tumor formation.
authors.affiliation: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Rm. 5D37, Bethesda, MD 20892, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Gläsker
authors.forename: Tae-Sung
authors.initials: TS
authors.lastname: Sohn
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okamoto
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D002893:Chromosomes, Human, Pair 3; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human