title: Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors.
abstract: OBJECTIVE
  To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.
  
  
  METHODS
  As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.
  
  
  RESULTS
  We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC.
  
  
  CONCLUSIONS
  Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.
authors.affiliation: Transgenomic, Gaithersburg, Maryland, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Erich
authors.initials: E
authors.lastname: Jaeger
authors.forename: Yangu
authors.initials: Y
authors.lastname: Shi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Durocher
authors.forename: Sunil
authors.initials: S
authors.lastname: Mahurkar
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Matveev
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.forename: Hellena
authors.initials: H
authors.lastname: Kollarova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.forename: Marie
authors.initials: M
authors.lastname: Navratilova
authors.forename: Neonilia
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: Anush
authors.initials: A
authors.lastname: Mukeria
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcatova
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Toro
authors.forename: Sara
authors.initials: S
authors.lastname: Karami
authors.forename: Rayjean
authors.initials: R
authors.lastname: Hung
authors.forename: Gary F
authors.initials: GF
authors.lastname: Gerard
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.forename: Frederic M
authors.initials: FM
authors.lastname: Waldman
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human