Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma
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. W...
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| Veröffentlicht in: | Blood 2002-05, Vol.99 (10), p.3562-3565 |
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| creator | Wiesener, Michael S. Seyfarth, Melchior Warnecke, Christina Jürgensen, Jan Steffen Rosenberger, Christian Morgan, Neil V. Maher, Eamonn R. Frei, Ulrich Eckardt, Kai-Uwe |
| description | 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-1α and HIF-2α. 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-1α to VHL, thus leading to accumulation of HIF, which drives EPO production. |
| doi_str_mv | 10.1182/blood.V99.10.3562 |
| format | Article |
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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-1α and HIF-2α. 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-1α to VHL, thus leading to accumulation of HIF, which drives EPO production.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood.V99.10.3562</identifier><identifier>PMID: 11986208</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Biological and medical sciences ; Carcinoma, Renal Cell - complications ; Carcinoma, Renal Cell - genetics ; Carcinoma, Renal Cell - metabolism ; Carcinoma, Renal Cell - pathology ; Diseases of red blood cells ; Erythropoietin - biosynthesis ; Erythropoietin - blood ; Erythropoietin - genetics ; Genes, Tumor Suppressor ; Hematologic and hematopoietic diseases ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; Kidney Neoplasms - complications ; Kidney Neoplasms - genetics ; Kidney Neoplasms - metabolism ; Kidney Neoplasms - pathology ; Kidneys ; Ligases - genetics ; Ligases - metabolism ; Male ; Medical sciences ; Middle Aged ; Myocardial Infarction - etiology ; Nephrology. Urinary tract diseases ; Point Mutation ; Polycythemia - blood ; Polycythemia - etiology ; Polycythemias ; RNA, Messenger - biosynthesis ; Tomography, X-Ray Computed ; Transcription Factors - biosynthesis ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Proteins ; Tumors of the urinary system ; Ubiquitin-Protein Ligases ; Von Hippel-Lindau Tumor Suppressor Protein</subject><ispartof>Blood, 2002-05, Vol.99 (10), p.3562-3565</ispartof><rights>2002 American Society of Hematology</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-c7d340c7e9e24935912cebc4d7bad3ab27c819b29d2000897213780438f72db83</citedby><cites>FETCH-LOGICAL-c470t-c7d340c7e9e24935912cebc4d7bad3ab27c819b29d2000897213780438f72db83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13661552$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11986208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wiesener, Michael S.</creatorcontrib><creatorcontrib>Seyfarth, Melchior</creatorcontrib><creatorcontrib>Warnecke, Christina</creatorcontrib><creatorcontrib>Jürgensen, Jan Steffen</creatorcontrib><creatorcontrib>Rosenberger, Christian</creatorcontrib><creatorcontrib>Morgan, Neil V.</creatorcontrib><creatorcontrib>Maher, Eamonn R.</creatorcontrib><creatorcontrib>Frei, Ulrich</creatorcontrib><creatorcontrib>Eckardt, Kai-Uwe</creatorcontrib><title>Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma</title><title>Blood</title><addtitle>Blood</addtitle><description>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-1α and HIF-2α. 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-1α to VHL, thus leading to accumulation of HIF, which drives EPO production.</description><subject>Biological and medical sciences</subject><subject>Carcinoma, Renal Cell - complications</subject><subject>Carcinoma, Renal Cell - genetics</subject><subject>Carcinoma, Renal Cell - metabolism</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>Diseases of red blood cells</subject><subject>Erythropoietin - biosynthesis</subject><subject>Erythropoietin - blood</subject><subject>Erythropoietin - genetics</subject><subject>Genes, Tumor Suppressor</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit</subject><subject>Kidney Neoplasms - complications</subject><subject>Kidney Neoplasms - genetics</subject><subject>Kidney Neoplasms - metabolism</subject><subject>Kidney Neoplasms - pathology</subject><subject>Kidneys</subject><subject>Ligases - genetics</subject><subject>Ligases - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Myocardial Infarction - etiology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Point Mutation</subject><subject>Polycythemia - blood</subject><subject>Polycythemia - etiology</subject><subject>Polycythemias</subject><subject>RNA, Messenger - biosynthesis</subject><subject>Tomography, X-Ray Computed</subject><subject>Transcription Factors - biosynthesis</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Suppressor Proteins</subject><subject>Tumors of the urinary system</subject><subject>Ubiquitin-Protein Ligases</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD2P1DAQhi0E4vYOfgANcgNdFn8kcSwqdAIOaSUogDaa2JNbo6wdbGfR9vxwnNuVrqOxPaNnXo0fQl5xtuW8E--GKQS7_an1tnRk04onZMMb0VWMCfaUbBhjbVVrxa_IdUq_GOO1FM1zcsW57lrBug35-w0ieAzzBCk7QzGe8j4Gc8ohuUQhpWAcZLT0j8t7Cp46Dya7I2Tn7-kcnM_0sORSBk_DSPMe6bE879w841TtnLew0Hv0WCYp0IgeJmpwKgdE43w4wAvybIQp4cvLfUN-fPr4_fau2n39_OX2w64ytWK5MsrKmhmFGkWtZaO5MDiY2qoBrIRBKNNxPQhtRfl5p5XgUnWslt2ohB06eUPennPnGH4vmHJ_cGldZTWwpF7xtpactwXkZ9DEkFLEsZ-jO0A89Zz1q_r-QX1f1K-dVX2ZeX0JX4YD2seJi-sCvLkAkAxMY_FuXHrkZNvyplmD3p85LCqODmOfjENv0LqIJvc2uP-s8Q8S26P-</recordid><startdate>20020515</startdate><enddate>20020515</enddate><creator>Wiesener, Michael S.</creator><creator>Seyfarth, Melchior</creator><creator>Warnecke, Christina</creator><creator>Jürgensen, Jan Steffen</creator><creator>Rosenberger, Christian</creator><creator>Morgan, Neil V.</creator><creator>Maher, Eamonn R.</creator><creator>Frei, Ulrich</creator><creator>Eckardt, Kai-Uwe</creator><general>Elsevier Inc</general><general>The Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20020515</creationdate><title>Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma</title><author>Wiesener, Michael S. ; Seyfarth, Melchior ; Warnecke, Christina ; Jürgensen, Jan Steffen ; Rosenberger, Christian ; Morgan, Neil V. ; Maher, Eamonn R. ; Frei, Ulrich ; Eckardt, Kai-Uwe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-c7d340c7e9e24935912cebc4d7bad3ab27c819b29d2000897213780438f72db83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Biological and medical sciences</topic><topic>Carcinoma, Renal Cell - complications</topic><topic>Carcinoma, Renal Cell - genetics</topic><topic>Carcinoma, Renal Cell - metabolism</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>Diseases of red blood cells</topic><topic>Erythropoietin - biosynthesis</topic><topic>Erythropoietin - blood</topic><topic>Erythropoietin - genetics</topic><topic>Genes, Tumor Suppressor</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit</topic><topic>Kidney Neoplasms - complications</topic><topic>Kidney Neoplasms - genetics</topic><topic>Kidney Neoplasms - metabolism</topic><topic>Kidney Neoplasms - pathology</topic><topic>Kidneys</topic><topic>Ligases - genetics</topic><topic>Ligases - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Myocardial Infarction - etiology</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Point Mutation</topic><topic>Polycythemia - blood</topic><topic>Polycythemia - etiology</topic><topic>Polycythemias</topic><topic>RNA, Messenger - biosynthesis</topic><topic>Tomography, X-Ray Computed</topic><topic>Transcription Factors - biosynthesis</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Suppressor Proteins</topic><topic>Tumors of the urinary system</topic><topic>Ubiquitin-Protein Ligases</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wiesener, Michael S.</creatorcontrib><creatorcontrib>Seyfarth, Melchior</creatorcontrib><creatorcontrib>Warnecke, Christina</creatorcontrib><creatorcontrib>Jürgensen, Jan Steffen</creatorcontrib><creatorcontrib>Rosenberger, Christian</creatorcontrib><creatorcontrib>Morgan, Neil V.</creatorcontrib><creatorcontrib>Maher, Eamonn R.</creatorcontrib><creatorcontrib>Frei, Ulrich</creatorcontrib><creatorcontrib>Eckardt, Kai-Uwe</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wiesener, Michael S.</au><au>Seyfarth, Melchior</au><au>Warnecke, Christina</au><au>Jürgensen, Jan Steffen</au><au>Rosenberger, Christian</au><au>Morgan, Neil V.</au><au>Maher, Eamonn R.</au><au>Frei, Ulrich</au><au>Eckardt, Kai-Uwe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2002-05-15</date><risdate>2002</risdate><volume>99</volume><issue>10</issue><spage>3562</spage><epage>3565</epage><pages>3562-3565</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><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-1α and HIF-2α. 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-1α to VHL, thus leading to accumulation of HIF, which drives EPO production.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>11986208</pmid><doi>10.1182/blood.V99.10.3562</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Biological and medical sciences Carcinoma, Renal Cell - complications Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - pathology Diseases of red blood cells Erythropoietin - biosynthesis Erythropoietin - blood Erythropoietin - genetics Genes, Tumor Suppressor Hematologic and hematopoietic diseases Humans Hypoxia-Inducible Factor 1, alpha Subunit Kidney Neoplasms - complications Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney Neoplasms - pathology Kidneys Ligases - genetics Ligases - metabolism Male Medical sciences Middle Aged Myocardial Infarction - etiology Nephrology. Urinary tract diseases Point Mutation Polycythemia - blood Polycythemia - etiology Polycythemias RNA, Messenger - biosynthesis Tomography, X-Ray Computed Transcription Factors - biosynthesis Transcription Factors - genetics Transcription Factors - metabolism Tumor Cells, Cultured Tumor Suppressor Proteins Tumors of the urinary system Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein |
| title | Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma |
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