Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma

Blood. 2002 May 15;99(10):3562-5. doi: 10.1182/blood.v99.10.3562.

Abstract

The von Hippel-Lindau (VHL) tumor suppressor gene targets hypoxia-inducible transcription factors (HIFs) for proteasomal degradation. Erythrocytosis due to inappropriate production of erythropoietin (EPO), one of the HIF target genes, is a classic albeit rare finding in patients with renal cancer. We report the clinical to molecular analysis in a patient in whom a thrombotic myocardial infarction was the first manifestation of a clear cell renal carcinoma associated with an elevated serum EPO level (109 U/L) and erythrocytosis (hemoglobin 200 g/L [20 g/dL]). The tumor strongly expressed EPO messenger RNA and the 2 regulatory subunits HIF-1alpha and HIF-2alpha. Sequence analysis of tumor tissue identified a point mutation of the VHL gene (nucleotide 701 T > C) with a predicted amino acid exchange (Leu163Pro). This structural change, although located at distance to the HIF-binding region, was found to inhibit binding of HIF-1alpha to VHL, thus leading to accumulation of HIF, which drives EPO production.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / complications*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Erythropoietin / biosynthesis
  • Erythropoietin / blood
  • Erythropoietin / genetics
  • Genes, Tumor Suppressor
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Kidney Neoplasms / complications*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Ligases / genetics*
  • Ligases / metabolism
  • Male
  • Middle Aged
  • Myocardial Infarction / etiology
  • Point Mutation*
  • Polycythemia / blood
  • Polycythemia / etiology*
  • RNA, Messenger / biosynthesis
  • Tomography, X-Ray Computed
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases*
  • Von Hippel-Lindau Tumor Suppressor Protein

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Erythropoietin
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ligases
  • VHL protein, human