title: Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma.
abstract: BACKGROUND
  Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-1alpha and -2alpha is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-1alpha and HIF-2alpha share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-1alpha expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-1alpha and HIF-2alpha contribute to renal tumourigenesis was investigated here.
  
  
  METHODS
  Mutation analysis of the complete coding sequence of HIF-1alpha and HIF-2alpha was carried out in primary RCC (n=40).
  
  
  RESULTS
  The analysis revealed a somatic HIF1A missense substitution, p.Val116Glu, in a single RCC. Functional studies demonstrated that p.Val116Glu impaired HIF-1alpha transcriptional activity. Genotyping of HIF1A variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls.
  
  
  CONCLUSIONS
  The detection of a loss-of-function HIF1A mutation in a primary RCC is consistent with HIF-1 and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIF1A are not frequently implicated in the pathogenesis of RCC.
authors.affiliation: Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morris
authors.forename: David J
authors.initials: DJ
authors.lastname: Hughes
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Tian
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Kah Weng
authors.initials: KW
authors.lastname: Lau
authors.forename: Dean
authors.initials: D
authors.lastname: Gentle
authors.forename: Salwati
authors.initials: S
authors.lastname: Shuib
authors.forename: Pablo
authors.initials: P
authors.lastname: Serrano-Fernandez
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human