Mutation of the von Hippel-Lindau (VHL) gene in human colorectal carcinoma: association with cytoplasmic accumulation of hypoxia-inducible factor (HIF)-1alpha

We screened for mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and examined the relationship of these mutations with expression of hypoxia-inducible factor (HIF)-1alpha protein in human colorectal carcinomas. DNAs were extracted from 130 paraffin-embedded tumor specimens and subjected to polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis followed by direct sequencing. We identified 13 mutations in the coding sequence of VHL, 12 of which were unique events. Three mutations were located in exon 2 and the others in exon 3. These mutations were detected in 10 of 88 (11.4%) tumors tested. Furthermore, seven of the 13 (53.8%) VHL mutants immunohistochemically showed high HIF-1alpha expression. The mean percentage of cells with strong cytoplasmic HIF-1alpha expression was 67.5% in tumors with VHL mutations, and this level was significantly higher than that in tumors without mutations (50.8%, P < 0.05). These findings suggest that mutations in VHL may play a role in colorectal carcinoma via activation of the HIF-related transcriptional cascade.