title: Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study.
abstract: BACKGROUND
  Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC). We studied the VHL mutation status in a large population-based case group.
  
  
  METHODS
  Cases were identified within the Netherlands cohort study on diet and cancer, which includes 120,852 men and women. After 11.3 years of follow-up, 337 incident cases with histologically confirmed epithelial cancers were identified. DNA was isolated from paraffin material collected from 51 pathology laboratories and revised by one pathologist, leaving material from 235 cases. VHL mutational status was assessed by SSCP followed by direct sequencing, after testing SSCP as a screening tool in a subsample.
  
  
  RESULTS
  The number of mutations was significantly higher for clear-cell RCC compared to other histological types. We observed 131 mutations in 114 out of 187 patients (61%) with clear-cell RCC. The majority of mutations were truncating mutations (47%). The mean tumor size was 72.7 mm for mutated tumors compared to 65.3 mm for wildtype tumors (p = 0.06). No statistically significant differences were observed for nuclear grade, TNM distribution or stage. In other histological types, we observed 8 mutations in 7 out of 48 patients (15%), 1 mutation in 1 of 6 oncocytoma, 3 mutations in 2 of 7 chromophobe RCC, 2 mutations in 2 of 30 papillary RCC, no mutations in 1 collecting duct carcinoma and 2 mutations in 2 of 4 unclassified RCC.
  
  
  CONCLUSIONS
  VHL mutations were detected in 61% of sporadic clear-cell RCC. VHL mutated and wildtype clear-cell RCC did not differ with respect to most parameters.
authors.affiliation: Department of Urology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. K.vanHouwelingen@ncmls.kun.nl
authors.forename: Kjeld P
authors.initials: KP
authors.lastname: van Houwelingen
authors.forename: Boukje A C
authors.initials: BA
authors.lastname: van Dijk
authors.forename: Christina A
authors.initials: CA
authors.lastname: Hulsbergen-van de Kaa
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Schouten
authors.forename: Hanneke J M
authors.initials: HJ
authors.lastname: Gorissen
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003062:Codon; D015331:Cohort Studies; D004247:DNA / Q000737:chemistry; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D011795:Surveys and Questionnaires; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D003062:Codon; D017931:DNA Primers; D004247:DNA; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human