Abstract
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 language | English |
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Pages (from-to) | 4337-4343 |
Number of pages | 7 |
Journal | Anticancer research |
Volume | 29 |
Issue number | 11 |
Publication status | Published - 1 Nov 2009 |
Keywords
- genetics
- Renal cell carcinoma
- hypoxia-inducible factors
- VHL