GTS5:Hereditary papillary renal carcinoma (MET): Difference between revisions

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 ==Definition/Description of Disease==
-Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span>
+Hereditary papillary renal cell carcinoma (HPRCC) is an autosomal dominant syndrome characterized by the occurrence of bilateral and multifocal, classic type papillary renal cell carcinomas. In 1994, Zbar and colleagues first described HPRCC in a family spanning three generations with 9 of 15 members who presented with bilateral papillary renal cell neoplasms. Subsequently, 41 patients in 10 families affected with papillary renal cell carcinomas were reported from the same group. <ref>{{Cite journal|last=Zbar|first=B.|last2=Tory|first2=K.|last3=Merino|first3=M.|last4=Schmidt|first4=L.|last5=Glenn|first5=G.|last6=Choyke|first6=P.|last7=Walther|first7=M. M.|last8=Lerman|first8=M.|last9=Linehan|first9=W. M.|date=1994-03|title=Hereditary papillary renal cell carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/8308957|journal=The Journal of Urology|volume=151|issue=3|pages=561–566|doi=10.1016/s0022-5347(17)35015-2|issn=0022-5347|pmid=8308957}}</ref><ref>{{Cite journal|last=Zbar|first=B.|last2=Glenn|first2=G.|last3=Lubensky|first3=I.|last4=Choyke|first4=P.|last5=Walther|first5=M. M.|last6=Magnusson|first6=G.|last7=Bergerheim|first7=U. S.|last8=Pettersson|first8=S.|last9=Amin|first9=M.|date=1995-03|title=Hereditary papillary renal cell carcinoma: clinical studies in 10 families|url=https://pubmed.ncbi.nlm.nih.gov/7853572|journal=The Journal of Urology|volume=153|issue=3 Pt 2|pages=907–912|issn=0022-5347|pmid=7853572}}</ref> HPRCC manifests exclusively in the kidney clinically. Non-renal manifestations associated with this syndrome have not been reported. HPRCC occurs over a wide age range from 19 to 66 years with median and mean ages of 41 and 42 years, respectively <ref>{{Cite journal|last=Shuch|first=Brian|last2=Vourganti|first2=Srinivas|last3=Ricketts|first3=Christopher J.|last4=Middleton|first4=Lindsay|last5=Peterson|first5=James|last6=Merino|first6=Maria J.|last7=Metwalli|first7=Adam R.|last8=Srinivasan|first8=Ramaprasad|last9=Linehan|first9=W. Marston|date=2014-02-10|title=Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management|url=https://pubmed.ncbi.nlm.nih.gov/24378414|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=32|issue=5|pages=431–437|doi=10.1200/JCO.2013.50.8192|issn=1527-7755|pmc=3912328|pmid=24378414}}</ref>,  but typically occur later than other forms of hereditary RCC. There is no sex predisposition and both male and female appear to be similarly affected. Family history of renal tumor is always present. HPRCC are mostly bilateral and multifocal, but renal cysts are less common compared to other hereditary RCC.<ref>{{Cite journal|last=Zbar|first=B.|last2=Glenn|first2=G.|last3=Lubensky|first3=I.|last4=Choyke|first4=P.|last5=Walther|first5=M. M.|last6=Magnusson|first6=G.|last7=Bergerheim|first7=U. S.|last8=Pettersson|first8=S.|last9=Amin|first9=M.|date=1995-03|title=Hereditary papillary renal cell carcinoma: clinical studies in 10 families|url=https://pubmed.ncbi.nlm.nih.gov/7853572|journal=The Journal of Urology|volume=153|issue=3 Pt 2|pages=907–912|issn=0022-5347|pmid=7853572}}</ref><ref>{{Cite journal|last=Metwalli|first=Adam R.|last2=Linehan|first2=William M.|date=2014-09|title=Nephron-sparing surgery for multifocal and hereditary renal tumors|url=https://pubmed.ncbi.nlm.nih.gov/25014245|journal=Current Opinion in Urology|volume=24|issue=5|pages=466–473|doi=10.1097/MOU.0000000000000094|issn=1473-6586|pmc=4441729|pmid=25014245}}</ref> Clinical presentation of HPRCC is similar to sporadic papillary renal cell carcinomas which are often detected incidentally or during screening of asymptomatic members of renal cell carcinoma families. Renal tumor in large size may present a classic triad of flank pain, hematuria, and an abdominal mass. Distant metastasis can rarely occur.<ref>{{Cite journal|last=Lubensky|first=I. A.|last2=Schmidt|first2=L.|last3=Zhuang|first3=Z.|last4=Weirich|first4=G.|last5=Pack|first5=S.|last6=Zambrano|first6=N.|last7=Walther|first7=M. M.|last8=Choyke|first8=P.|last9=Linehan|first9=W. M.|date=1999-08|title=Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype|url=https://pubmed.ncbi.nlm.nih.gov/10433944|journal=The American Journal of Pathology|volume=155|issue=2|pages=517–526|doi=10.1016/S0002-9440(10)65147-4|issn=0002-9440|pmc=1866853|pmid=10433944}}</ref>
 ==Epidemiology/Prevalence==
-Put your text here
+A novel pathogenic variant was identified in exon 16 of the ''MET'' gene in two large hereditary papillary renal carcinoma (HPRC) families in North America. Affected members of the two families shared the same haplotype located within and immediately distal to the ''MET'' gene, suggesting a common ancestor (founder effect)<ref>{{Cite journal|last=Schmidt|first=L.|last2=Junker|first2=K.|last3=Weirich|first3=G.|last4=Glenn|first4=G.|last5=Choyke|first5=P.|last6=Lubensky|first6=I.|last7=Zhuang|first7=Z.|last8=Jeffers|first8=M.|last9=Vande Woude|first9=G.|date=1998-04-15|title=Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene|url=https://pubmed.ncbi.nlm.nih.gov/9563489|journal=Cancer Research|volume=58|issue=8|pages=1719–1722|issn=0008-5472|pmid=9563489}}</ref> However, HPRC families with identical germline ''MET'' pathogenic variants who do not share a common ancestral haplotype have also been reported<ref>{{Cite journal|last=Schmidt|first=Laura S.|last2=Nickerson|first2=Michael L.|last3=Angeloni|first3=Debora|last4=Glenn|first4=Gladys M.|last5=Walther|first5=McClellan M.|last6=Albert|first6=Paul S.|last7=Warren|first7=Michelle B.|last8=Choyke|first8=Peter L.|last9=Torres-Cabala|first9=Carlos A.|date=2004-10|title=Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene|url=https://pubmed.ncbi.nlm.nih.gov/15371818|journal=The Journal of Urology|volume=172|issue=4 Pt 1|pages=1256–1261|doi=10.1097/01.ju.0000139583.63354.e0|issn=0022-5347|pmid=15371818}}</ref>
 ==Genetic Abnormalities: Germline==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.'')</span>
+The ''MET'' gene is located on chromosome 7q31.2 and encodes a protein with 1,390 amino-acids.[1] The functional MET receptor is a heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa). The primary single-chain precursor protein is posttranslationally cleaved to produce the alpha and beta subunits,<ref>{{Cite journal|last=Komada|first=M.|last2=Hatsuzawa|first2=K.|last3=Shibamoto|first3=S.|last4=Ito|first4=F.|last5=Nakayama|first5=K.|last6=Kitamura|first6=N.|date=1993-08-09|title=Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin|url=https://pubmed.ncbi.nlm.nih.gov/8344430|journal=FEBS letters|volume=328|issue=1-2|pages=25–29|doi=10.1016/0014-5793(93)80958-w|issn=0014-5793|pmid=8344430}}</ref> which are disulfide-linked to form the mature receptor. Two transcript variants, which encode different isoforms, have been found for this gene.The beta subunit of MET possesses tyrosine kinase activity and was identified as the cell-surface receptor for hepatocyte growth factor (HGF).<ref>{{Cite journal|last=Bottaro|first=D. P.|last2=Rubin|first2=J. S.|last3=Faletto|first3=D. L.|last4=Chan|first4=A. M.|last5=Kmiecik|first5=T. E.|last6=Vande Woude|first6=G. F.|last7=Aaronson|first7=S. A.|date=1991-02-15|title=Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product|url=https://pubmed.ncbi.nlm.nih.gov/1846706|journal=Science (New York, N.Y.)|volume=251|issue=4995|pages=802–804|doi=10.1126/science.1846706|issn=0036-8075|pmid=1846706}}</ref> MET transduces signals from the extracellular matrix into the cytoplasm by binding to the HGF ligand; it also regulates cell proliferation, scattering, morphogenesis, and survival.[4] Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain, which provides docking sites for downstream signaling molecules. After activation by its ligand, MET interacts with the PI3K subunit PI3KR1, PLCG1, SRC, GRB2, or STAT3, or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades, including RAS-ERK, PI3K/AKT, and PLC-gamma/PKC.<ref>{{Cite journal|last=Gherardi|first=Ermanno|last2=Birchmeier|first2=Walter|last3=Birchmeier|first3=Carmen|last4=Vande Woude|first4=George|date=2012-01-24|title=Targeting MET in cancer: rationale and progress|url=https://pubmed.ncbi.nlm.nih.gov/22270953|journal=Nature Reviews. Cancer|volume=12|issue=2|pages=89–103|doi=10.1038/nrc3205|issn=1474-1768|pmid=22270953}}</ref> The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities<ref>{{Cite journal|last=Gherardi|first=Ermanno|last2=Birchmeier|first2=Walter|last3=Birchmeier|first3=Carmen|last4=Vande Woude|first4=George|date=2012-01-24|title=Targeting MET in cancer: rationale and progress|url=https://pubmed.ncbi.nlm.nih.gov/22270953|journal=Nature Reviews. Cancer|volume=12|issue=2|pages=89–103|doi=10.1038/nrc3205|issn=1474-1768|pmid=22270953}}</ref>
+Expression was autosomal dominant with incomplete penetrance. These tumors are often bilateral and multifocal ranging from papillary adenomas to papillary renal cell carcinomas. Noting that these tumors had a papillary morphology, often retained trisomy chromosome 17 and 7 with a partial duplication of the mutant MET allele of 7q21-q35, and yet lacked chromosome 3p deletion, these tumors were postulated to be molecularly distinct from sporadic papillary renal cell carcinoma
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