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

Mark R. Morris, David J. Hughes, Ya Min Tian, Christopher J. Ricketts, Kah Weng Lau, Dean Gentle, Salwati Shuib, Pablo Serrano-Fernandez, Jan Lubinski, Michael S. Wiesener, Christopher W. Pugh, Farida Latif, Peter J. Ratcliffe, Eamonn R. Maher

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-Iα and -2α is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-Ia and HIF-2a share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-Ia expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-Ia and HlF-2a contribute to renal tumourigenesis was investigated here. Materials and Methods: Mutation analysis of the complete coding sequence of HIF-Ia and HlF-2α was carried out in primary RCC (n=40). Results: The analysis revealed a somatic HIFlA missense substitution, p.VaU16Glu, in a single RCC. Functional studies demonstrated that p.VallloGlu impaired HIF-Ia transcriptional activity. Genotyping of HIFlA variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls. Conclusion: The detection of a loss-of-function HIFlA mutation in a primary RCC is consistent with HIF-I and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIFlA are not frequently implicated in the pathogenesis of RCC.

Original languageEnglish
Pages (from-to)4337-4343
Number of pages7
JournalAnticancer Research
Volume29
Issue number11
Publication statusPublished - Nov 2009
Externally publishedYes

Fingerprint

Renal Cell Carcinoma
Transcription Factors
Mutation
Kidney
Hypoxia
Tumor Cell Line
Tumor Suppressor Genes
Growth
Genes

Keywords

  • Genetics
  • Hypoxia-inducible factors
  • Renal cell carcinoma
  • VHL

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Morris, M. R., Hughes, D. J., Tian, Y. M., Ricketts, C. J., Lau, K. W., Gentle, D., ... Maher, E. R. (2009). Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Research, 29(11), 4337-4343.

Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. / Morris, Mark R.; Hughes, David J.; Tian, Ya Min; Ricketts, Christopher J.; Lau, Kah Weng; Gentle, Dean; Shuib, Salwati; Serrano-Fernandez, Pablo; Lubinski, Jan; Wiesener, Michael S.; Pugh, Christopher W.; Latif, Farida; Ratcliffe, Peter J.; Maher, Eamonn R.

In: Anticancer Research, Vol. 29, No. 11, 11.2009, p. 4337-4343.

Research output: Contribution to journalArticle

Morris, MR, Hughes, DJ, Tian, YM, Ricketts, CJ, Lau, KW, Gentle, D, Shuib, S, Serrano-Fernandez, P, Lubinski, J, Wiesener, MS, Pugh, CW, Latif, F, Ratcliffe, PJ & Maher, ER 2009, 'Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma', Anticancer Research, vol. 29, no. 11, pp. 4337-4343.
Morris MR, Hughes DJ, Tian YM, Ricketts CJ, Lau KW, Gentle D et al. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Research. 2009 Nov;29(11):4337-4343.
Morris, Mark R. ; Hughes, David J. ; Tian, Ya Min ; Ricketts, Christopher J. ; Lau, Kah Weng ; Gentle, Dean ; Shuib, Salwati ; Serrano-Fernandez, Pablo ; Lubinski, Jan ; Wiesener, Michael S. ; Pugh, Christopher W. ; Latif, Farida ; Ratcliffe, Peter J. ; Maher, Eamonn R. / Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. In: Anticancer Research. 2009 ; Vol. 29, No. 11. pp. 4337-4343.
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abstract = "Background: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-Iα and -2α is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-Ia and HIF-2a share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-Ia expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-Ia and HlF-2a contribute to renal tumourigenesis was investigated here. Materials and Methods: Mutation analysis of the complete coding sequence of HIF-Ia and HlF-2α was carried out in primary RCC (n=40). Results: The analysis revealed a somatic HIFlA missense substitution, p.VaU16Glu, in a single RCC. Functional studies demonstrated that p.VallloGlu impaired HIF-Ia transcriptional activity. Genotyping of HIFlA variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls. Conclusion: The detection of a loss-of-function HIFlA mutation in a primary RCC is consistent with HIF-I and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIFlA are not frequently implicated in the pathogenesis of RCC.",
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T1 - Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma

AU - Morris, Mark R.

AU - Hughes, David J.

AU - Tian, Ya Min

AU - Ricketts, Christopher J.

AU - Lau, Kah Weng

AU - Gentle, Dean

AU - Shuib, Salwati

AU - Serrano-Fernandez, Pablo

AU - Lubinski, Jan

AU - Wiesener, Michael S.

AU - Pugh, Christopher W.

AU - Latif, Farida

AU - Ratcliffe, Peter J.

AU - Maher, Eamonn R.

PY - 2009/11

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N2 - Background: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-Iα and -2α is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-Ia and HIF-2a share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-Ia expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-Ia and HlF-2a contribute to renal tumourigenesis was investigated here. Materials and Methods: Mutation analysis of the complete coding sequence of HIF-Ia and HlF-2α was carried out in primary RCC (n=40). Results: The analysis revealed a somatic HIFlA missense substitution, p.VaU16Glu, in a single RCC. Functional studies demonstrated that p.VallloGlu impaired HIF-Ia transcriptional activity. Genotyping of HIFlA variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls. Conclusion: The detection of a loss-of-function HIFlA mutation in a primary RCC is consistent with HIF-I and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIFlA are not frequently implicated in the pathogenesis of RCC.

AB - Background: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-Iα and -2α is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-Ia and HIF-2a share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-Ia expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-Ia and HlF-2a contribute to renal tumourigenesis was investigated here. Materials and Methods: Mutation analysis of the complete coding sequence of HIF-Ia and HlF-2α was carried out in primary RCC (n=40). Results: The analysis revealed a somatic HIFlA missense substitution, p.VaU16Glu, in a single RCC. Functional studies demonstrated that p.VallloGlu impaired HIF-Ia transcriptional activity. Genotyping of HIFlA variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls. Conclusion: The detection of a loss-of-function HIFlA mutation in a primary RCC is consistent with HIF-I and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIFlA are not frequently implicated in the pathogenesis of RCC.

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