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Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma

  • Authors:
    • Claire Taylor
    • Rachel A. Craven
    • Patricia Harnden
    • Peter J. Selby
    • Rosamonde E. Banks
  • View Affiliations / Copyright

    Affiliations: Cancer Research UK Cancer Centre Genomics Facility, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK, Clinical and Biomedical Proteomics Group, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK, Department of Histopathology, St. James's University Hospital, Leeds, UK
    Copyright: © Taylor et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 1229-1240
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    Published online on: July 20, 2012
       https://doi.org/10.3892/ijo.2012.1561
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Abstract

Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumour suppressor gene are common in sporadic conventional (clear cell) renal cell carcinoma (ccRCC). The effects on VHL expression are unknown but increased understanding may be relevant clinically, either in terms of prognosis or in therapy selection. We have examined the expression of VHL mutant RNA in 84 ccRCC tumours previously screened for mutations in genomic DNA, 56 of which contained 52 unique mutations or polymorphisms. Based on the predicted change to the primary amino acid sequence, 24 of the mutations were missense, 11 resulted in frameshifts with premature truncation, 9 resulted in immediate truncation at the site of the mutation and 2 were frameshifts which extended the reading frame beyond the normal stop codon. Nine tumours had intronic variants, including substitution of invariant residues at splice sites, deletion of nucleotides spanning the exon-intron junction, an intronic variant of unknown function and the polymorphism c.463+43A>G. Four variants were identified which were present in genomic DNA but not in mRNA. Three of these, all encoding apparent missense changes to the primary amino acid sequence, were located close to the ends of exons, reduced the strength of the splice site and function as null rather than missense variants. One nonsense variant was not detectable in mRNA but all other mutations resulting in premature truncation codons (PTCs) were, suggesting truncating VHL mutations may potentially generate truncated VHL protein. An intronic variant, c.341‑11T>A, previously regarded as of unknown function, is associated with an increased level of skipping of exon 2 and may, therefore, reduce production of pVHL. Our data show that the biological consequences of VHL mutations are not necessarily predictable from the sequence change of the mutation and that for the majority of VHL mutations, the potential for the generation of mutant protein exists.
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Copy and paste a formatted citation
Spandidos Publications style
Taylor C, Craven RA, Harnden P, Selby PJ and Banks R : Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. Int J Oncol 41: 1229-1240, 2012.
APA
Taylor, C., Craven, R.A., Harnden, P., Selby, P.J., & Banks, R. . (2012). Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. International Journal of Oncology, 41, 1229-1240. https://doi.org/10.3892/ijo.2012.1561
MLA
Taylor, C., Craven, R. A., Harnden, P., Selby, P. J., Banks, R. ."Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma". International Journal of Oncology 41.4 (2012): 1229-1240.
Chicago
Taylor, C., Craven, R. A., Harnden, P., Selby, P. J., Banks, R. ."Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma". International Journal of Oncology 41, no. 4 (2012): 1229-1240. https://doi.org/10.3892/ijo.2012.1561
Copy and paste a formatted citation
x
Spandidos Publications style
Taylor C, Craven RA, Harnden P, Selby PJ and Banks R : Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. Int J Oncol 41: 1229-1240, 2012.
APA
Taylor, C., Craven, R.A., Harnden, P., Selby, P.J., & Banks, R. . (2012). Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. International Journal of Oncology, 41, 1229-1240. https://doi.org/10.3892/ijo.2012.1561
MLA
Taylor, C., Craven, R. A., Harnden, P., Selby, P. J., Banks, R. ."Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma". International Journal of Oncology 41.4 (2012): 1229-1240.
Chicago
Taylor, C., Craven, R. A., Harnden, P., Selby, P. J., Banks, R. ."Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma". International Journal of Oncology 41, no. 4 (2012): 1229-1240. https://doi.org/10.3892/ijo.2012.1561
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