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

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+[[GTS5:Table_of_Contents|Genetic Tumour Syndromes (Who Classification, 5th ed.)]]
 {{Under Construction}}
 <span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
 ==Primary Author(s)*==
-Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
+Farid Ullah, MS, PhD
 ==WHO Classification of Disease==
-<span style="color:#0070C0">(''Instructions: This table’s content from the WHO book will be <u>autocompleted</u>.'')</span>
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 |-
 |Book
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+|Genetic Tumour Syndromes (5th ed.)
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 |Category
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+|Growth factor receptors and related signalling pathways
 |-
 |Family
-|
+|Growth factor receptors
 |-
 |Type
-|
+|Hereditary papillary renal carcinoma (MET)
 |-
 |Subtype(s)
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+|N/A
 |}
 ==Related Terminology==
-<span style="color:#0070C0">(''Instructions: This table will have the related terminology from the WHO book <u>autocompleted</u>.)''</span>
 {| class="wikitable"
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 |Acceptable
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+|N/A
 |-
 |Not Recommended
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+|N/A
 |}
 ==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
 {| class="wikitable sortable"
 |-
-!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity
+!Gene
+! !!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity
 !Notes
 |-
-|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Many||<span class="blue-text">EXAMPLE:</span> Multiple variant types leading to loss of function||<span class="blue-text">EXAMPLE:</span> Autosomal recessive,
+|''MET''
-~30% penetrant for carriers
+| ||Missense
-|
+T3640C (M1149D)
-|-
-|<span class="blue-text">EXAMPLE:</span> Gene X
+G3810T (V1206L)
-|<span class="blue-text">EXAMPLE:</span> List the specific mutation
-|
+G3906A (V1238I)
-|
-|
+G3930A (D1246N)
-|-
-|
+A3937G (Y1248C)
-|
+|The tumorigenic hallmark of HPRCC is ''MET'' germline proto-oncogene mutations, which are often missense, leading to activation of the tyrosine kinase domain of c-MET sans endogenous HGF/SF. The activation subsequently triggers downstream signaling pathways that promote cell survival, proliferation, angiogenesis and inhibition of apoptosis.||Dominant,
-|
+HPRC is highly penetrant (approaching 100%)
-|
 |
 |}
-==Genetic Abnormalities: Somatic==
+==Genetic Abnormalities: Somatic Mutation Tumor==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.'')</span>
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 !Notes
 |-
-|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Biallelic inactivation variants||<span class="blue-text">EXAMPLE:</span> Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.||
+|''MET''||Missense
-|
+C3831G (L1213V)
-|-
-|<span class="blue-text">EXAMPLE:</span> ''BRCA1''
+G3930C (D1246H)
-|<span class="blue-text">EXAMPLE:</span> Reversion mutation
-|<span class="blue-text">EXAMPLE:</span> After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.
+T3936C (Y1248H)
-|
-|
+T3997C (M1268D
-|-
+| ||Somatic
-|
-|
-|
-|
 |
 |}
 ==Genes and Main Pathways Involved==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
+Hippo, mTOR or p53
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 Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
 ==References==
-(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
+(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span><references />
 ==Notes==
 <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 Prior Author(s):
-[[Category:GTS5]][[Category:DISEASE]]
+[[Category:GTS5]]
+[[Category:DISEASE]]