Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma.
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.
Morris
Mark R
MR
Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK.
Hughes
David J
DJ
Tian
Ya-Min
YM
Ricketts
Christopher J
CJ
Lau
Kah Weng
KW
Gentle
Dean
D
Shuib
Salwati
S
Serrano-Fernandez
Pablo
P
Lubinski
Jan
J
Wiesener
Michael S
MS
Pugh
Christopher W
CW
Latif
Farida
F
Ratcliffe
Peter J
PJ
Maher
Eamonn R
ER
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
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human