VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.

Abstract

Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

• Authors: Francesca Lessi, Chiara Maria Mazzanti, Sara Tomei, Claudio Di Cristofano, Andrea Minervini, Michele Menicagli, Alessandro Apollo, Lorenzo Masieri, Paola Collecchi, Riccardo Minervini, Marco Carini, Generoso Bevilacqua
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 31 Issue 3 Pg. 840 (Mar 2014) ISSN: 1559-131X [Electronic] United States
• PMID: 24446253 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• DNA Mutational Analysis
• Female
• Follow-Up Studies
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Immunoenzyme Techniques
• Kidney Neoplasms (genetics, metabolism, pathology)
• Loss of Heterozygosity
• Male
• Middle Aged
• Mutation (genetics)
• Neoplasm Staging
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Promoter Regions, Genetic
• Tissue Array Analysis
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)