Mutation Analysis of Hypoxia-inducible Factors HIF1A and HIF2A in Renal Cell Carcinoma

Mark Morris, DJ Hughes, YM Tian, Christopher Ricketts, KW Lau, Dean Gentle, S Shuib, P Serrano-Fernandez, J Lubinski, MS Wiesener, CW Pugh, Farida Latif, PJ Ratcliffe, Eamonn Maher

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50 Citations (Scopus)


Background: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-1 alpha and -2 alpha is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-1 alpha and HIF-2 alpha share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-1 alpha expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-1 alpha and HIF-2 alpha contribute to renal tumourigenesis was investigated here. Materials and Methods: Mutation analysis of the complete coding sequence of HIF-1 alpha and HIF-2 alpha 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-1 alpha 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.
Original languageEnglish
Pages (from-to)4337-4343
Number of pages7
JournalAnticancer research
Issue number11
Publication statusPublished - 1 Nov 2009


  • genetics
  • Renal cell carcinoma
  • hypoxia-inducible factors
  • VHL


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