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. 2005 Aug 19;95(2):149–153. doi: 10.1111/j.1349-7006.2004.tb03196.x

Mutation of the von Hippel‐Lindau (VHL) gene in human colorectal carcinoma: Association with cytoplasmic accumulation of hypoxia‐inducible factor (HIF)‐1α

Toshio Kuwai 1, Yasuhiko Kitadai 1,✉, Shinji Tanaka 2, Toru Hiyama 1, Keiji Tanimoto 3, Kazuaki Chayama 1
PMCID: PMC11159487  PMID: 14965365

Abstract

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)‐1α protein in human colorectal carcinomas. DNAs were extracted from 130 paraffin‐embedded tumor specimens and subjected to poly‐merase 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‐1α expression. The mean percentage of cells with strong cytoplasmic HIF‐1α 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.

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