Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma.

Journal article

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.

Authors: Morris, MR; Hughes, D; Tian, Y; Ricketts, C; Lau, K

• Publication status: Published
• Journal: Anticancer research
• Volume: 29
• Issue: 11
• Pages: 4337-4343
• Publication date: 2009-11-01
• EISSN: 1791-7530
• ISSN: 0250-7005
• Language: English
• Keywords: Carcinoma, Renal Cell; Case-Control Studies; Basic Helix-Loop-Helix Transcription Factors; DNA Mutational Analysis; Hypoxia-Inducible Factor 1, alpha Subunit; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Germ-Line Mutation; Mutation, Missense; Humans; Kidney Neoplasms