Renal cell carcinoma pathophysiology: Difference between revisions

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==Overview==
==Overview==
The pathophysiology of renal cell carcinomas plays an important role in differentiating between the types of renal cell carcinomas and in choosing appropriate targeted medical therapies. Sporadic forms of clear cell renal carcinomas, the most common form of renal cell carcinomas, have similar pathophysiological mechanisms to those of von Hippel-Lindau (VHL) disease. On the other hand, ''MET'' [[proto-oncogene]] seems to play a role in the disease pathogenesis of papillary forms of renal cell carcinoma. Uniquely also, oncocytomas are benign tumors that arise from type A intercalated cells, whereas chromophobe renal cell carcinoma arises from type B intercalated cells.
The [[pathophysiology]] of renal cell carcinomas plays an important role in differentiating between the types of renal cell carcinomas and in choosing appropriate targeted medical therapies. Sporadic forms of clear cell renal carcinomas, the most common form of renal cell carcinomas, have similar pathophysiological mechanisms to those of [[Von Hippel-Lindau Disease|von Hippel-Lindau]] (VHL) disease. On the other hand, ''MET'' [[proto-oncogene]] seems to play a role in the disease [[pathogenesis]] of papillary forms of renal cell carcinoma. Uniquely also, [[Oncocytoma|oncocytomas]] are [[benign tumors]] that arise from type A intercalated cells, whereas [[chromophobe]] renal cell carcinoma arises from type B intercalated cells.


==Pathophysiology==
==Pathophysiology==
===Sporadic Forms of Clear Cell Renal Carcinoma===
===Sporadic Forms of Clear Cell Renal Carcinoma===
Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the ''VHL'' gene - a tumor suppressor gene -  and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal ''VHL'' gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>


VHL protein is an oxygen sensing regulator of hypoxic responses. It has a major role in binding and inhibiting transciptional activators hypoxia-induced factor (HIF) 1-alpha and 2-alpha via ubiquination and destruction using elongin proteins C and B that bind to cul2 protein of the ubiquitin ligase protein (cullin) family.<ref name="pmid7585187">{{cite journal| author=Iliopoulos O, Kibel A, Gray S, Kaelin WG| title=Tumour suppression by the human von Hippel-Lindau gene product. | journal=Nat Med | year= 1995 | volume= 1 | issue= 8 | pages= 822-6 | pmid=7585187 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585187  }} </ref><ref name="pmid7585510">{{cite journal| author=Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L et al.| title=Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 21 | pages= 4804-7 | pmid=7585510 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585510  }} </ref><ref name="pmid8855223">{{cite journal| author=Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA| title=Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. | journal=Proc Natl Acad Sci U S A | year= 1996 | volume= 93 | issue= 20 | pages= 10595-9 | pmid=8855223 | doi= | pmc=PMC38198 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8855223  }} </ref><ref name="pmid10823831">{{cite journal| author=Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC et al.| title=Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. | journal=J Biol Chem | year= 2000 | volume= 275 | issue= 33 | pages= 25733-41 | pmid=10823831 | doi=10.1074/jbc.M002740200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10823831  }} </ref><ref name="pmid10878807">{{cite journal| author=Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE et al.| title=Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. | journal=Nat Cell Biol | year= 2000 | volume= 2 | issue= 7 | pages= 423-7 | pmid=10878807 | doi=10.1038/35017054 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10878807  }} </ref><ref name="pmid10944113">{{cite journal| author=Tanimoto K, Makino Y, Pereira T, Poellinger L| title=Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. | journal=EMBO J | year= 2000 | volume= 19 | issue= 16 | pages= 4298-309 | pmid=10944113 | doi=10.1093/emboj/19.16.4298 | pmc=PMC302039 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944113  }} </ref> Normally, inhibition of HIF by VHL prevents the encoding of proteins that promote angiogenesis, such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-alpha), glucose receptors such as GLUT-1 glucose transporter, and carbonic anhydrase IX (CA9) which ensures acid-base balance.<ref name="pmid7585187">{{cite journal| author=Iliopoulos O, Kibel A, Gray S, Kaelin WG| title=Tumour suppression by the human von Hippel-Lindau gene product. |journal=Nat Med | year= 1995 | volume= 1 | issue= 8 | pages= 822-6 | pmid=7585187 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585187  }} </ref><ref name="pmid7585510">{{cite journal| author=Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L et al.| title=Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 21 | pages= 4804-7 |pmid=7585510 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585510  }} </ref> Inhibition of VHL induces the overexpression of these proteins, mimicking hypoxemia, and facilitates the development of clear cell carcinoma.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref> The disease process is not believed to be due to the simple interaction between VHL protein and HIF. Other proteins are also thought to be involved in the process, including fibronectin<ref name="pmid9651579">{{cite journal| author=Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN et al.| title=The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. | journal=Mol Cell | year= 1998 | volume= 1 | issue= 7 | pages= 959-68 | pmid=9651579 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9651579  }} </ref>, chaperonin TRiC/CCT<ref name="pmid14636579">{{cite journal| author=Feldman DE, Spiess C, Howard DE, Frydman J| title=Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. | journal=Mol Cell | year= 2003 | volume= 12 | issue= 5 | pages= 1213-24 | pmid=14636579 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14636579  }} </ref>, microtubules<ref name="pmid12510195">{{cite journal| author=Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W| title=Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. | journal=Nat Cell Biol | year= 2003 | volume= 5 | issue= 1 | pages= 64-70 | pmid=12510195 | doi=10.1038/ncb899 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12510195  }} </ref>, and transcription factor Jade-1<ref name="pmid12169691">{{cite journal| author=Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT| title=The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. | journal=J Biol Chem | year= 2002 | volume= 277 | issue= 42 | pages= 39887-98 | pmid=12169691 | doi=10.1074/jbc.M205040200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12169691  }} </ref><ref name="pmid14973063">{{cite journal| author=Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT| title=Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. | journal=Cancer Res | year= 2004 | volume= 64 | issue= 4 | pages= 1278-86 | pmid=14973063 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14973063  }} </ref><ref name="pmid16046545">{{cite journal| author=Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H et al.| title=Jade-1, a candidate renal tumor suppressor that promotes apoptosis. | journal=Proc Natl Acad Sci U S A | year= 2005 | volume= 102 | issue= 31 | pages= 11035-40 | pmid=16046545 | doi=10.1073/pnas.0500757102 | pmc=PMC1182408 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16046545  }} </ref>.
* Although [[Von Hippel-Lindau Disease|Von Hippel-Lindau]] (VHL), an [[autosomal dominant]] disorder, is characterized by the mutation of the [[Von Hippel-Lindau tumor suppressor|''VHL'' gene]] - a [[tumor suppressor gene]] -  and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal ''[[Von Hippel–Lindau tumor suppressor|VHL]]'' [[gene]], the [[gene]] itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>
 
* [[VHL|VHL protein]] is an [[oxygen]] sensing regulator of [[hypoxic]] responses. It has a major role in binding and inhibiting transciptional activators hypoxia-induced factor (HIF) 1-alpha and 2-alpha via ubiquination and destruction using elongin proteins C and B that bind to cul2 protein of the ubiquitin ligase protein (cullin) family.<ref name="pmid7585187">{{cite journal| author=Iliopoulos O, Kibel A, Gray S, Kaelin WG| title=Tumour suppression by the human von Hippel-Lindau gene product. | journal=Nat Med | year= 1995 | volume= 1 | issue= 8 | pages= 822-6 | pmid=7585187 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585187  }} </ref><ref name="pmid7585510">{{cite journal| author=Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L et al.| title=Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 21 | pages= 4804-7 | pmid=7585510 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585510  }} </ref><ref name="pmid8855223">{{cite journal| author=Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA| title=Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. | journal=Proc Natl Acad Sci U S A | year= 1996 | volume= 93 | issue= 20 | pages= 10595-9 | pmid=8855223 | doi= | pmc=PMC38198 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8855223  }} </ref><ref name="pmid10823831">{{cite journal| author=Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC et al.| title=Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. | journal=J Biol Chem | year= 2000 | volume= 275 | issue= 33 | pages= 25733-41 | pmid=10823831 | doi=10.1074/jbc.M002740200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10823831  }} </ref><ref name="pmid10878807">{{cite journal| author=Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE et al.| title=Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. | journal=Nat Cell Biol | year= 2000 | volume= 2 | issue= 7 | pages= 423-7 | pmid=10878807 | doi=10.1038/35017054 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10878807  }} </ref><ref name="pmid10944113">{{cite journal| author=Tanimoto K, Makino Y, Pereira T, Poellinger L| title=Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. | journal=EMBO J | year= 2000 | volume= 19 | issue= 16 | pages= 4298-309 | pmid=10944113 | doi=10.1093/emboj/19.16.4298 | pmc=PMC302039 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944113  }} </ref>  
* Normally, inhibition of HIF by [[Von Hippel–Lindau tumor suppressor|VHL]] prevents the encoding of proteins that promote [[angiogenesis]], such as [[vascular endothelial growth factor]] ([[Vascular endothelial growth factor|VEGF]]), [[transforming growth factor alpha]] ([[Transforming growth factor alpha|TGF-alpha]]), glucose receptors such as [[GLUT1|GLUT-1 glucose transporter]], and [[CA9|carbonic anhydrase IX]] ([[CA9]]) which ensures acid-base balance.<ref name="pmid7585187">{{cite journal| author=Iliopoulos O, Kibel A, Gray S, Kaelin WG| title=Tumour suppression by the human von Hippel-Lindau gene product. |journal=Nat Med | year= 1995 | volume= 1 | issue= 8 | pages= 822-6 | pmid=7585187 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585187  }} </ref><ref name="pmid7585510">{{cite journal| author=Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L et al.| title=Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 21 | pages= 4804-7 |pmid=7585510 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585510  }} </ref> Inhibition of VHL induces the overexpression of these proteins, mimicking [[hypoxemia]], and facilitates the development of clear cell carcinoma.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref> The disease process is not believed to be due to the simple interaction between VHL protein and HIF. Other proteins are also thought to be involved in the process, including [[fibronectin]]<ref name="pmid9651579">{{cite journal| author=Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN et al.| title=The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. | journal=Mol Cell | year= 1998 | volume= 1 | issue= 7 | pages= 959-68 | pmid=9651579 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9651579  }} </ref>, chaperonin TRiC/CCT<ref name="pmid14636579">{{cite journal| author=Feldman DE, Spiess C, Howard DE, Frydman J| title=Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. | journal=Mol Cell | year= 2003 | volume= 12 | issue= 5 | pages= 1213-24 | pmid=14636579 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14636579  }} </ref>, [[microtubules]]<ref name="pmid12510195">{{cite journal| author=Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W| title=Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. | journal=Nat Cell Biol | year= 2003 | volume= 5 | issue= 1 | pages= 64-70 | pmid=12510195 | doi=10.1038/ncb899 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12510195  }} </ref>, and transcription factor Jade-1<ref name="pmid12169691">{{cite journal| author=Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT| title=The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. | journal=J Biol Chem | year= 2002 | volume= 277 | issue= 42 | pages= 39887-98 | pmid=12169691 | doi=10.1074/jbc.M205040200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12169691  }} </ref><ref name="pmid14973063">{{cite journal| author=Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT| title=Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. | journal=Cancer Res | year= 2004 | volume= 64 | issue= 4 | pages= 1278-86 | pmid=14973063 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14973063  }} </ref><ref name="pmid16046545">{{cite journal| author=Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H et al.| title=Jade-1, a candidate renal tumor suppressor that promotes apoptosis. | journal=Proc Natl Acad Sci U S A | year= 2005 | volume= 102 | issue= 31 | pages= 11035-40 | pmid=16046545 | doi=10.1073/pnas.0500757102 | pmc=PMC1182408 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16046545  }} </ref>.


===Familial Forms of Clear Cell Renal Carcinoma===
===Familial Forms of Clear Cell Renal Carcinoma===
The translocation and loss of chromosome 3p at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to VHL disease.<ref name="pmid470981">{{cite journal| author=Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC et al.| title=Hereditary renal-cell carcinoma associated with a chromosomal translocation. | journal=N Engl J Med | year= 1979 | volume= 301 | issue= 11 | pages= 592-5 | pmid=470981 | doi=10.1056/NEJM197909133011107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=470981  }} </ref>
 
* The [[Translocations|translocation]] and loss of [[Chromosome 3 (human)|chromosome 3p]] at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to [[VHL gene]].<ref name="pmid470981">{{cite journal| author=Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC et al.| title=Hereditary renal-cell carcinoma associated with a chromosomal translocation. | journal=N Engl J Med | year= 1979 | volume= 301 | issue= 11 | pages= 592-5 | pmid=470981 | doi=10.1056/NEJM197909133011107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=470981  }} </ref>


===Papillary Renal Cell Carcinoma===
===Papillary Renal Cell Carcinoma===
It is believed that chromosomal aberrations, including the duplication of chromosome 7 encoding ''MET'' proto-oncogene, a tyrosine kinase activated by hepatocyte growth factor, may contribute to sporadic cases of papillary renal cell carcinoma in a small percentage of cases.<ref name="pmid9195569">{{cite journal| author=Delahunt B, Eble JN| title=Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. | journal=Mod Pathol | year= 1997 | volume= 10 | issue= 6 | pages= 537-44 | pmid=9195569 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9195569  }} </ref><ref name="pmid14559804">{{cite journal| author=Gunawan B, von Heydebreck A, Fritsch T, Huber W, Ringert RH, Jakse G et al.| title=Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors. | journal=Cancer Res | year= 2003 | volume= 63 | issue= 19 | pages= 6200-5 | pmid=14559804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14559804  }} </ref><ref name="pmid10433944">{{cite journal| author=Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N et al.| title=Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. | journal=Am J Pathol | year= 1999 | volume= 155 | issue= 2 | pages= 517-26 | pmid=10433944 | doi=10.1016/S0002-9440(10)65147-4 | pmc=PMC1866853 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10433944  }} </ref><ref name="pmid9140397">{{cite journal| author=Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P et al.| title=Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. | journal=Nat Genet | year= 1997 | volume= 16 | issue= 1 | pages= 68-73 | pmid=9140397 | doi=10.1038/ng0597-68 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9140397  }} </ref> On the other hand, hereditary forms of papillary cell carcinoma have a different pathophysiology. Hereditary forms have an autosomal dominant pattern.<ref name="pmid7853572">{{cite journal| author=Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G et al.| title=Hereditary papillary renal cell carcinoma: clinical studies in 10 families. | journal=J Urol | year= 1995 | volume= 153 | issue= 3 Pt 2 | pages= 907-12 | pmid=7853572 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7853572  }} </ref> In hereditary forms, pathological cellular transformation is facilitated by MET auto-activation due to the duplication of chromosome 7.<ref name="pmid9731534">{{cite journal| author=Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E et al.| title=Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. | journal=Nat Genet | year= 1998 | volume= 20 | issue= 1 | pages= 66-9 | pmid=9731534 | doi=10.1038/1727 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9731534  }} </ref><ref name="pmid9715275">{{cite journal| author=Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F et al.| title=Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. | journal=Oncogene | year= 1998 | volume= 17 | issue= 6 | pages= 733-9 | pmid=9715275 | doi=10.1038/sj.onc.1201983 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9715275  }} </ref>
 
* It is believed that chromosomal aberrations, including the duplication of [[chromosome 7]] encoding ''MET'' proto-oncogene, a [[tyrosine kinase]] activated by [[hepatocyte growth factor]], may contribute to sporadic cases of papillary renal cell carcinoma in a small percentage of cases.<ref name="pmid9195569">{{cite journal| author=Delahunt B, Eble JN| title=Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. | journal=Mod Pathol | year= 1997 | volume= 10 | issue= 6 | pages= 537-44 | pmid=9195569 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9195569  }} </ref><ref name="pmid14559804">{{cite journal| author=Gunawan B, von Heydebreck A, Fritsch T, Huber W, Ringert RH, Jakse G et al.| title=Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors. | journal=Cancer Res | year= 2003 | volume= 63 | issue= 19 | pages= 6200-5 | pmid=14559804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14559804  }} </ref><ref name="pmid10433944">{{cite journal| author=Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N et al.| title=Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. | journal=Am J Pathol | year= 1999 | volume= 155 | issue= 2 | pages= 517-26 | pmid=10433944 | doi=10.1016/S0002-9440(10)65147-4 | pmc=PMC1866853 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10433944  }} </ref><ref name="pmid9140397">{{cite journal| author=Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P et al.| title=Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. | journal=Nat Genet | year= 1997 | volume= 16 | issue= 1 | pages= 68-73 | pmid=9140397 | doi=10.1038/ng0597-68 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9140397  }} </ref>  
* On the other hand, hereditary forms of papillary cell carcinoma have a different [[pathophysiology]]. Hereditary forms have an [[autosomal dominant]] pattern.<ref name="pmid7853572">{{cite journal| author=Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G et al.| title=Hereditary papillary renal cell carcinoma: clinical studies in 10 families. | journal=J Urol | year= 1995 | volume= 153 | issue= 3 Pt 2 | pages= 907-12 | pmid=7853572 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7853572  }} </ref> In hereditary forms, pathological cellular transformation is facilitated by MET auto-activation due to the duplication of [[chromosome 7]].<ref name="pmid9731534">{{cite journal| author=Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E et al.| title=Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. | journal=Nat Genet | year= 1998 | volume= 20 | issue= 1 | pages= 66-9 | pmid=9731534 | doi=10.1038/1727 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9731534  }} </ref><ref name="pmid9715275">{{cite journal| author=Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F et al.| title=Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. | journal=Oncogene | year= 1998 | volume= 17 | issue= 6 | pages= 733-9 | pmid=9715275 | doi=10.1038/sj.onc.1201983 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9715275  }} </ref>


Papillary renal cell carcinoma has 2 histologic types:
Papillary renal cell carcinoma has 2 histologic types:
Line 28: Line 33:
|+ '''''Types of Papillary Renal Cell Carcinoma<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>'''''
|+ '''''Types of Papillary Renal Cell Carcinoma<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>'''''


| bgcolor="#d9ff54" |'''Type''' || bgcolor="#d9ff54" |'''Cell Size''' || bgcolor="#d9ff54" |'''Cytoplasm''' || bgcolor="#d9ff54" |'''Nucleus'''|| bgcolor="#d9ff54" |'''Nucleolus'''
| style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Type''' || style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Cell Size''' || style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Cytoplasm''' || style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Nucleus'''|| style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Nucleolus'''
|-
|-
| bgcolor="#ececec" |'''Type I''' || Small || Pale || Small and oval || Indistinct
| bgcolor="#DCDCDC" |'''Type I''' || Small || Pale || Small and oval || Indistinct
|-
|-
| bgcolor="#ececec" |'''Type II''' || Large || Abundant eosinophilic || Large and spherical || Distinct
| bgcolor="#DCDCDC" |'''Type II''' || Large || Abundant eosinophilic || Large and spherical || Distinct
|}
|}
<sup><center>Adapted from Cohen HT, McGovern FJ. Renal-cell carcinoma. ''N Engl J Med''. 2005 Dec 8;353(23):2477-90</center>
<sup><center>Adapted from Cohen HT, McGovern FJ. Renal-cell carcinoma. ''N Engl J Med''. 2005 Dec 8;353(23):2477-90</center></sup>


===Oncocytoma and Chromophobe Renal Cell Carcinoma===
===Oncocytoma and Chromophobe Renal Cell Carcinoma===
Oncocytomas are benign tumors that arise from type A intercalated cells, whereas chromophobe renal cell carcinoma arises from type B intercalated cells.<ref name="pmid16339096">{{cite journal|author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 |volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref> Occasionally, oncocytomas and chromophobe renal cell carcinoma are associated with Birt-Hogg-Dube (BHD) syndrome. The ''BHD'' gene encodes folliculin, a tumor suppressor protein.<ref name="pmid12204536">{{cite journal| author=Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML et al.| title=Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. | journal=Cancer Cell | year= 2002 | volume= 2 | issue= 2 | pages= 157-64 | pmid=12204536 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12204536  }} </ref><ref name="pmid12907635">{{cite journal| author=Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K et al.| title=Inactivation of BHD in sporadic renal tumors. | journal=Cancer Res | year= 2003 | volume= 63 | issue= 15 | pages= 4583-7 | pmid=12907635 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12907635  }} </ref><ref name="pmid14627671">{{cite journal| author=da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER| title=Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. | journal=J Med Genet | year= 2003 | volume= 40 | issue= 11 | pages= 820-4 | pmid=14627671 | doi= | pmc=PMC1735328 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14627671  }} </ref>
 
* Oncocytomas are [[benign tumors]] that arise from type A [[intercalated cells]], whereas [[chromophobe]] renal cell carcinoma arises from type B [[intercalated cells]].<ref name="pmid16339096">{{cite journal|author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 |volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>  
* Occasionally, oncocytomas and [[chromophobe]] renal cell carcinoma are associated with [[Birt-Hogg-Dubé syndrome|Birt-Hogg-Dube (BHD) syndrome]]. The [[BHD|''BHD'' gene]] encodes [[folliculin]], a [[Tumor suppressor|tumor suppressor protein]].<ref name="pmid12204536">{{cite journal| author=Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML et al.| title=Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. | journal=Cancer Cell | year= 2002 | volume= 2 | issue= 2 | pages= 157-64 | pmid=12204536 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12204536  }} </ref><ref name="pmid12907635">{{cite journal| author=Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K et al.| title=Inactivation of BHD in sporadic renal tumors. | journal=Cancer Res | year= 2003 | volume= 63 | issue= 15 | pages= 4583-7 | pmid=12907635 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12907635  }} </ref><ref name="pmid14627671">{{cite journal| author=da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER| title=Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. | journal=J Med Genet | year= 2003 | volume= 40 | issue= 11 | pages= 820-4 | pmid=14627671 | doi= | pmc=PMC1735328 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14627671  }} </ref>


===Collecting Duct Renal Cell Carcinoma===
===Collecting Duct Renal Cell Carcinoma===
Collecting duct renal cell carcinomas are aggressive malignant tumors. It resembles transitional cell carcinomas. Medullary carcinoma, a variant of collecting duct renal cell carcinoma, is associated with sickle cell disease and trait.<ref name="pmid16339096">{{cite journal|author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 |volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>
 
* Collecting duct renal cell carcinomas are aggressive [[malignant]] tumors. It resembles transitional cell carcinomas. [[Medullary carcinoma]], a variant of collecting duct renal cell carcinoma, is associated with [[sickle cell disease]] and [[Category: (name of the system)]]  trait.<ref name="pmid16339096">{{cite journal|author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 |volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>


==References==
==References==
{{Reflist|}}
{{Reflist|2}}


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Overview

The pathophysiology of renal cell carcinomas plays an important role in differentiating between the types of renal cell carcinomas and in choosing appropriate targeted medical therapies. Sporadic forms of clear cell renal carcinomas, the most common form of renal cell carcinomas, have similar pathophysiological mechanisms to those of von Hippel-Lindau (VHL) disease. On the other hand, MET proto-oncogene seems to play a role in the disease pathogenesis of papillary forms of renal cell carcinoma. Uniquely also, oncocytomas are benign tumors that arise from type A intercalated cells, whereas chromophobe renal cell carcinoma arises from type B intercalated cells.

Pathophysiology

Sporadic Forms of Clear Cell Renal Carcinoma

  • Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the VHL gene - a tumor suppressor gene - and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal VHL gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.[1]

Familial Forms of Clear Cell Renal Carcinoma

  • The translocation and loss of chromosome 3p at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to VHL gene.[14]

Papillary Renal Cell Carcinoma

Papillary renal cell carcinoma has 2 histologic types:

Types of Papillary Renal Cell Carcinoma[1]
Type Cell Size Cytoplasm Nucleus Nucleolus
Type I Small Pale Small and oval Indistinct
Type II Large Abundant eosinophilic Large and spherical Distinct
Adapted from Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005 Dec 8;353(23):2477-90

Oncocytoma and Chromophobe Renal Cell Carcinoma

Collecting Duct Renal Cell Carcinoma

References

  1. 1.0 1.1 1.2 1.3 1.4 Cohen HT, McGovern FJ (2005). "Renal-cell carcinoma". N Engl J Med. 353 (23): 2477–90. doi:10.1056/NEJMra043172. PMID 16339096.
  2. 2.0 2.1 Iliopoulos O, Kibel A, Gray S, Kaelin WG (1995). "Tumour suppression by the human von Hippel-Lindau gene product". Nat Med. 1 (8): 822–6. PMID 7585187.
  3. 3.0 3.1 Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L; et al. (1995). "Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene". Cancer Res. 55 (21): 4804–7. PMID 7585510.
  4. Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA (1996). "Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein". Proc Natl Acad Sci U S A. 93 (20): 10595–9. PMC 38198. PMID 8855223.
  5. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC; et al. (2000). "Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein". J Biol Chem. 275 (33): 25733–41. doi:10.1074/jbc.M002740200. PMID 10823831.
  6. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE; et al. (2000). "Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein". Nat Cell Biol. 2 (7): 423–7. doi:10.1038/35017054. PMID 10878807.
  7. Tanimoto K, Makino Y, Pereira T, Poellinger L (2000). "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein". EMBO J. 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. PMC 302039. PMID 10944113.
  8. Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN; et al. (1998). "The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix". Mol Cell. 1 (7): 959–68. PMID 9651579.
  9. Feldman DE, Spiess C, Howard DE, Frydman J (2003). "Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding". Mol Cell. 12 (5): 1213–24. PMID 14636579.
  10. Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W (2003). "Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL". Nat Cell Biol. 5 (1): 64–70. doi:10.1038/ncb899. PMID 12510195.
  11. Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT (2002). "The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1". J Biol Chem. 277 (42): 39887–98. doi:10.1074/jbc.M205040200. PMID 12169691.
  12. Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT (2004). "Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent". Cancer Res. 64 (4): 1278–86. PMID 14973063.
  13. Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H; et al. (2005). "Jade-1, a candidate renal tumor suppressor that promotes apoptosis". Proc Natl Acad Sci U S A. 102 (31): 11035–40. doi:10.1073/pnas.0500757102. PMC 1182408. PMID 16046545.
  14. Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC; et al. (1979). "Hereditary renal-cell carcinoma associated with a chromosomal translocation". N Engl J Med. 301 (11): 592–5. doi:10.1056/NEJM197909133011107. PMID 470981.
  15. Delahunt B, Eble JN (1997). "Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors". Mod Pathol. 10 (6): 537–44. PMID 9195569.
  16. Gunawan B, von Heydebreck A, Fritsch T, Huber W, Ringert RH, Jakse G; et al. (2003). "Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors". Cancer Res. 63 (19): 6200–5. PMID 14559804.
  17. Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N; et al. (1999). "Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype". Am J Pathol. 155 (2): 517–26. doi:10.1016/S0002-9440(10)65147-4. PMC 1866853. PMID 10433944.
  18. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P; et al. (1997). "Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas". Nat Genet. 16 (1): 68–73. doi:10.1038/ng0597-68. PMID 9140397.
  19. Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G; et al. (1995). "Hereditary papillary renal cell carcinoma: clinical studies in 10 families". J Urol. 153 (3 Pt 2): 907–12. PMID 7853572.
  20. Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E; et al. (1998). "Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas". Nat Genet. 20 (1): 66–9. doi:10.1038/1727. PMID 9731534.
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