title: Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location.
abstract: von Hippel Lindau disease (VHL) is an autosomal dominant familial cancer syndrome linked to alteration of the VHL tumor suppressor gene. Affected patients are predisposed to develop pheochromocytomas and cystic and solid tumors of the kidney, CNS, pancreas, retina, and epididymis. However, organ involvement varies considerably among families and has been shown to correlate with the underlying germline alteration. Clinically, we observed a paradoxically lower prevalence of renal cell carcinoma (RCC) in patients with complete germline deletion of VHL. To determine if a relationship existed between the type of VHL deletion and disease, we retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions, by history and radiographic imaging. Each individual and family was scored for cystic or solid involvement of CNS, pancreas, and kidney, and for pheochromocytoma. Germline deletions were mapped using a combination of fluorescent in situ hybridization (FISH) and quantitative Southern and Southern blot analysis. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9 vs. 22.6%, p=0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p=0.22), pancreas (p=0.72), or pheochromocytoma (p=0.34). Deletion mapping revealed that development of RCC had an even greater correlation with retention of HSPC300 (C3orf10), located within the 30-kb region of chromosome 3p, immediately telomeric to VHL (52.3 vs. 18.9%, p <0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. Careful correlation of genotypic data with objective phenotypic measures will provide further insight into the mechanisms of tumor formation.
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Maranchie
authors.forename: Anoushka
authors.initials: A
authors.lastname: Afonso
authors.forename: Paul S
authors.initials: PS
authors.lastname: Albert
authors.forename: Sivaram
authors.initials: S
authors.lastname: Kalyandrug
authors.forename: John L
authors.initials: JL
authors.lastname: Phillips
authors.forename: Shubo
authors.initials: S
authors.lastname: Zhou
authors.forename: James
authors.initials: J
authors.lastname: Peterson
authors.forename: Bijan M
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Katheen
authors.initials: K
authors.lastname: Hurley
authors.forename: Joseph
authors.initials: J
authors.lastname: Riss
authors.forename: James R
authors.initials: JR
authors.lastname: Vasselli
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: McClellan M
authors.initials: MM
authors.lastname: Walther
authors.forename: Richard D
authors.initials: RD
authors.lastname: Klausner
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D000328:Adult; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics*; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D017384:Sequence Deletion; D006623:von Hippel-Lindau Disease / Q000150:complications*