Somatic mutations of the von Hippel -- Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma |
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Authors: | Foster Keith; Prowse Amanda; van den Berg Anke; Fleming Stewart; Hulsbeek Miriam MF; Crossey Paul A; Richards Frances M; Cairns Paul; Affara Nabeel A; Ferguson-Smith Malcolm A; Buys Charles HCM; Maher Eamonn R |
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Institution: | Cambridge University Department of Pathology Cambridge, UK
1Department of Medical Genetics, University of Groningen, Groningen, the Netherlands
2Department of Pathology, University of Edinburgh Edinburgh, UK
3Head and Neck Cancer Research Division, Johns Hopkins University Baltimore. MD, USA |
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Abstract: | Loss of heterozygosity (LOH) studies have suggested that somaticmutations of a tumour suppressor gene or genes on chromosome3p are a critical event In the pathogenesls of non-familialrenal cell carcinoma (RCC). Germllne mutations of the von Hippel Lindau (VHL) disease gene predispose to early onsetand multifocal clear cell renal cell carcinoma, and the mechanismof tumorigenesls In VHL disease is consistent with a one-hitmutation model. To Investigate the role of somatic VHL genemutations in non-familial RCC, we analysed 99 primary RCC forVHL gene mutations by SSCP and heteroduplex analysis. SomaticVHL gene mutations were Identified In 30 of 65 (46%) sporadicRCC with chromosome 3p allele loss and one of 34 (3%) tumourswith no LOH for chromosome 3p. The VHL gene mutations were heterogeneous(17 frameshift deletions, eight missense mutations, four frameshiftinsertions, one nonsense and one splice site mutation), butno mutations were detected in the first 120 codons of clonedcoding sequence. Most RCCs with somatic VHL mutations (23 of27 (85%) informative cases) had chromosome 3p25 allele lossin the region of the VHL gene so that both alleles of the VHLgene had been inactivated as expected from a twohit modelof tumorigenesis. Detailed histopathology was available for59 of the tumours investigated: 18 of 43 (42%) RCC with a clearcell appearance had a somatic VHL gene mutation but none of16 nonclear cell RCC (eight chromophilic, three chromophobeand five oncocytoma) (x2= 7.77, P<0.025). These results suggestthat somatic mutations of the VHL gene are a critical eventin the pathogenesis of non-familial clear cell renal carcinoma,but do not exclude a role for other chromosome 3p tumour suppressorgenes. |
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