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

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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.

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Authors and Affiliations

  1. Pisa Science Foundation, Via Castaldi, 2, 56100, Pisa, Italy

    Francesca Lessi & Chiara Maria Mazzanti

  2. Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Doha, Qatar

    Sara Tomei

  3. Department of Experimental Medicine, Sapienza University of Rome, Polo Pontino, I.C.O.T., Latina, Italy

    Claudio Di Cristofano

  4. Department of Urology, Careggi Hospital, University of Florence, Florence, Italy

    Andrea Minervini, Lorenzo Masieri & Marco Carini

  5. Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University Hospital of Pisa, University of Pisa, Pisa, Italy

    Michele Menicagli, Alessandro Apollo, Paola Collecchi & Generoso Bevilacqua

  6. Division of Urology, Department of Surgery, University Hospital of Pisa, University of Pisa, Pisa, Italy

    Riccardo Minervini

Authors
  1. Francesca Lessi
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  2. Chiara Maria Mazzanti
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  3. Sara Tomei
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  4. Claudio Di Cristofano
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  5. Andrea Minervini
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Correspondence to Francesca Lessi.

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Lessi, F., Mazzanti, C.M., Tomei, S. et al. VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma. Med Oncol 31, 840 (2014). https://doi.org/10.1007/s12032-014-0840-8

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  • DOI: https://doi.org/10.1007/s12032-014-0840-8

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