TY - JOUR
T1 - Paraneoplastic erythrocytosis associated with an inactivating point-mutation of the von Hippel-Lindau gene in a renal cell carcinoma
AU - Wiesener, M
AU - Seyfarth, M
AU - Warnecke, C
AU - Jurgensen, JS
AU - Rosenberger, C
AU - Morgan, Neil
AU - Maher, Eamonn
AU - Frei, U
AU - Eckardt, K-U
PY - 2002/5/15
Y1 - 2002/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037092950&partnerID=8YFLogxK
U2 - 10.1182/blood.V99.10.3562
DO - 10.1182/blood.V99.10.3562
M3 - Article
C2 - 11986208
SN - 1528-0020
VL - 99
SP - 3562
EP - 3565
JO - Blood
JF - Blood
IS - 10
ER -