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. MATERIALS AND 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. CONCLUSION: 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.