title: Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.
abstract: von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273: 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76: 381-391, 1997; W. M. Linehan and R. D. Klausner, In: B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55: 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4: 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5: 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33: 328-332, 1996; B. Zbar, Cancer Surv., 25: 219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12: 417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families: two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in one family. In sum, FISH was found to be a simple and reliable method to detect VHL germline deletions and practically useful in cases where other methods of screening have failed to detect a VHL gene abnormality.
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Pack
authors.forename: B
authors.initials: B
authors.lastname: Zbar
authors.forename: E
authors.initials: E
authors.lastname: Pak
authors.forename: D O
authors.initials: DO
authors.lastname: Ault
authors.forename: J S
authors.initials: JS
authors.lastname: Humphrey
authors.forename: T
authors.initials: T
authors.lastname: Pham
authors.forename: K
authors.initials: K
authors.lastname: Hurley
authors.forename: R J
authors.initials: RJ
authors.lastname: Weil
authors.forename: W S
authors.initials: WS
authors.lastname: Park
authors.forename: I
authors.initials: I
authors.lastname: Kuzmin
authors.forename: C
authors.initials: C
authors.lastname: Stolle
authors.forename: G
authors.initials: G
authors.lastname: Glenn
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
authors.forename: M I
authors.initials: MI
authors.lastname: Lerman
authors.forename: R D
authors.initials: RD
authors.lastname: Klausner
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
authors.forename: Z
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D002893:Chromosomes, Human, Pair 3; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D008957:Models, Genetic; D017354:Point Mutation; D006623:von Hippel-Lindau Disease / Q000235:genetics*