Vascular endothelial growth factor overexpression is correlated with von Hippel-Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma

BACKGROUND: A high frequency of genetic alterations of the von Hippel-Lindau (VHL) gene and overexpression of the vascular endothelial growth factor (VEGF) gene have been observed independently in human sporadic renal cell carcinoma (RCCs), but to the authors' knowledge the association between the two has not been characterized in primary sporadic RCC. In the current study the authors report the simultaneous comparison of the biallelic inactivation status of the VHL gene and VEGF expression levels in patients with sporadic RCC. METHODS: DNA and RNA were extracted from 27 sporadic RCC samples. Mutation was analyzed by direct sequencing of the amplified VHL DNA and cDNA. Loss of heterozygosity (LOH) of the gene was analyzed at three polymorphic markers. The VEGF mRNA was measured using Northern blot analysis. RESULTS: Mutations of the VHL gene were found in 14 of 27 RCC samples (51.9%). LOH analysis by a VHL-intragenic polymorphic marker and 2 extragenic microsatellite markers, D3S1560 and D3S1317, showed that LOH occurred in 10 of 15 RCC samples (66.7%). Overexpression of VEGF mRNA was observed in 17 of 27 RCC cases (63.0%): 15 of the 18 RCC samples estimated to have at least 1 hit, but only 2 of the 6 RCC samples with 0-1 hit, and none of the 3 RCC samples in which the VHL gene was not inactivated. CONCLUSIONS: VEGF overexpression was found to be correlated with both monoallelic and biallelic VHL inactivation. Alteration of the VHL gene is believed to cause angiogenesis in RCC cases through the overexpression of VEGF.