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

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

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20 Citations (Scopus)


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.

Original languageEnglish
Article number840
JournalMedical Oncology
Issue number3
Publication statusPublished - 1 Jan 2014
Externally publishedYes



  • ccRCC
  • HIF-1α
  • Renal carcinoma
  • VHL

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Lessi, F., Mazzanti, C. M., Tomei, S., Di Cristofano, C., Minervini, A., Menicagli, M., Apollo, A., Masieri, L., Collecchi, P., Minervini, R., Carini, M., & Bevilacqua, G. (2014). VHL and HIF-1α: Gene variations and prognosis in early-stage clear cell renal cell carcinoma. Medical Oncology, 31(3), [840]. https://doi.org/10.1007/s12032-014-0840-8