title: Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma.
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.
authors: Department of Nephrology and Medical Intensive Care, Charité, Humboldt-University, Berlin, Germany.
authors: Michael S
authors: MS
authors: Wiesener
authors: Melchior
authors: M
authors: Seyfarth
authors: Christina
authors: C
authors: Warnecke
authors: Jan Steffen
authors: JS
authors: Jürgensen
authors: Christian
authors: C
authors: Rosenberger
authors: Neil V
authors: NV
authors: Morgan
authors: Eamonn R
authors: ER
authors: Maher
authors: Ulrich
authors: U
authors: Frei
authors: Kai-Uwe
authors: KU
authors: Eckardt
mesh_terms: D002292:Carcinoma, Renal Cell / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008025:Ligases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D017354:Point Mutation; D011086:Polycythemia / Q000097:blood / Q000209:etiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D004921:Erythropoietin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human