K. Foster et al., SOMATIC MUTATIONS OF THE VON HIPPEL-LINDAU DISEASE TUMOR-SUPPRESSOR GENE IN NONFAMILIAL CLEAR-CELL RENAL-CARCINOMA, Human molecular genetics, 3(12), 1994, pp. 2169-2173
Loss of heterozygosity (LOH) studies have suggested that somatic mutat
ions of a tumour suppressor gene or genes on chromosome 3p are a criti
cal event in the pathogenesis of non-familial renal cell carcinoma (RC
C). Germline mutations of the von Hippel - Lindau (VHL) disease gene p
redispose to early onset and multifocal clear cell renal cell carcinom
a, and the mechanism of tumorigenesis in VHL disease is consistent wit
h a one-hit mutation model. To investigate the role of somatic VHL gen
e mutations in non-famitial RCC, we analysed 99 primary RCC for VHL ge
ne mutations by SSCP and heteroduplex analysis. Somatic VHL gene mutat
ions were identified in 30 of 65 (46%) sporadic RCC with chromosome 3p
allele loss and one of 34 (3%) tumours with no LOH for chromosome 3p.
The VHL gene mutations were heterogeneous (17 frameshift deletions, e
ight missense mutations, four frameshift insertions, one nonsense and
one splice site mutation), but no mutations were detected in the first
120 codons of cloned coding sequence. Most RCCs with somatic VHL muta
tions (23 of 27 (85%) informative cases) had chromosome 3p25 allele lo
ss in the region of the VHL gene so that both alleles of the VHL gene
had been inactivated as expected from a two-hit model of tumorigenesis
. Detailed histopathology was available for 59 of the tumours investig
ated: 18 of 43 (42%) RCC with a clear cell appearance had a somatic VH
L gene mutation but none of 16 non-clear cell RCC (eight chromophilic,
three chromophobe and five oncocytoma) (chi 2 = 7.77, P<0.025). These
results suggest that somatic mutations of the VHL gene are a critical
event in the pathogenesis of non-familial clear cell renal carcinoma,
but do not exclude a role for other chromosome 3p tumour suppressor g
enes.