GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms
GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB,...
Gespeichert in:
| Veröffentlicht in: | The Journal of pathology 2022-06, Vol.257 (2), p.158-171 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 171 |
|---|---|
| container_issue | 2 |
| container_start_page | 158 |
| container_title | The Journal of pathology |
| container_volume | 257 |
| creator | Salles, Daniela C Asrani, Kaushal Woo, Juhyung Vidotto, Thiago Liu, Hans B Vidal, Igor Matoso, Andres Netto, George J Argani, Pedram Lotan, Tamara L |
| description | GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2‐associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR–Cas9 genome editing as well as in a mouse model of Tsc2 inactivation‐driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3‐ or TFEB‐driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low‐grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE‐ and mTORC1‐dependent fashion. Renal tumors in Tsc2+/− A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p |
| doi_str_mv | 10.1002/path.5875 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9310781</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2659002452</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4435-18b5db12ace4d2669069fb37a33a06e77b6237914d0070ea0d3edf9dee07639e3</originalsourceid><addsrcrecordid>eNp1kc1u1DAUhS0EokNhwQugSGxgkY5_EjveIJURtEgtrSCsLSe-oR45cWpnCrPjEXjGPkmdTlsBEqu7uJ8-naOD0EuCDwjGdDnq6eKgrET5CC0IljyXleSP0SL9aM4KIvbQsxjXGGMpy_Ip2mMlFlQWYoHWR-efT99n8HMMEKP1Q2YNDJPtLMSs_roiS7rs67Mv179-6xh9a_UEJtODyU5tnXW6t26bTUEP0flWT0mQSBPsFQxZgEG7bAA_Oh37-Bw96bSL8OLu7qNvHz_Uq-P85Ozo0-rwJG-LgpU5qZrSNITqFgpDOZeYy65hQjOmMQchGk6ZkKQwGAsMGhsGppMGAAvOJLB99G7nHTdND6ZNdYJ2agy212GrvLbq789gL9R3f6UkI1hUJAne3AmCv9xAnFRvYwvO6dRlExXllBaiomRGX_-Drv0mpNozVco0QFHSRL3dUW3wMQboHsIQrOYF1bygmhdM7Ks_0z-Q95MlYLkDflgH2_-b1PlhfXyrvAG_76iw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2659002452</pqid></control><display><type>article</type><title>GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms</title><source>Wiley Online Library - AutoHoldings Journals</source><source>MEDLINE</source><creator>Salles, Daniela C ; Asrani, Kaushal ; Woo, Juhyung ; Vidotto, Thiago ; Liu, Hans B ; Vidal, Igor ; Matoso, Andres ; Netto, George J ; Argani, Pedram ; Lotan, Tamara L</creator><creatorcontrib>Salles, Daniela C ; Asrani, Kaushal ; Woo, Juhyung ; Vidotto, Thiago ; Liu, Hans B ; Vidal, Igor ; Matoso, Andres ; Netto, George J ; Argani, Pedram ; Lotan, Tamara L</creatorcontrib><description>GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2‐associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR–Cas9 genome editing as well as in a mouse model of Tsc2 inactivation‐driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3‐ or TFEB‐driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low‐grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE‐ and mTORC1‐dependent fashion. Renal tumors in Tsc2+/− A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration‐associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration‐associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB‐transcriptional targets as diagnostic markers. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</description><identifier>ISSN: 0022-3417</identifier><identifier>EISSN: 1096-9896</identifier><identifier>DOI: 10.1002/path.5875</identifier><identifier>PMID: 35072947</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Angiomyolipoma ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics ; Biomarkers, Tumor - analysis ; Biomarkers, Tumor - genetics ; Carcinoma, Renal Cell - pathology ; CRISPR ; Eye Proteins ; Female ; Genome editing ; Genomes ; GPNMB ; Humans ; Image processing ; Immunohistochemistry ; Kidney cancer ; Kidney Neoplasms - pathology ; Kidneys ; Leukemia, Myeloid, Acute - genetics ; Leukocytes (eosinophilic) ; Male ; Mechanistic Target of Rapamycin Complex 1 ; Membrane Glycoproteins - genetics ; Mice ; Microphthalmia ; Microphthalmos - genetics ; Original ; Perivascular Epithelioid Cell Neoplasms - genetics ; Renal cell carcinoma ; TFE3 ; TFEB ; TOR protein ; TOR Serine-Threonine Kinases - genetics ; Transcription ; Transcription Factors - genetics ; translocation renal cell carcinoma ; Translocation, Genetic ; TSC1/2 ; Tuberous Sclerosis ; Tuberous Sclerosis Complex 1 ; Tuberous Sclerosis Complex 2 ; Tumorigenesis ; Tumors</subject><ispartof>The Journal of pathology, 2022-06, Vol.257 (2), p.158-171</ispartof><rights>2022 The Authors. published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</rights><rights>2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</rights><rights>2022. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4435-18b5db12ace4d2669069fb37a33a06e77b6237914d0070ea0d3edf9dee07639e3</citedby><cites>FETCH-LOGICAL-c4435-18b5db12ace4d2669069fb37a33a06e77b6237914d0070ea0d3edf9dee07639e3</cites><orcidid>0000-0002-0494-9067 ; 0000-0003-1904-185X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpath.5875$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpath.5875$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35072947$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Salles, Daniela C</creatorcontrib><creatorcontrib>Asrani, Kaushal</creatorcontrib><creatorcontrib>Woo, Juhyung</creatorcontrib><creatorcontrib>Vidotto, Thiago</creatorcontrib><creatorcontrib>Liu, Hans B</creatorcontrib><creatorcontrib>Vidal, Igor</creatorcontrib><creatorcontrib>Matoso, Andres</creatorcontrib><creatorcontrib>Netto, George J</creatorcontrib><creatorcontrib>Argani, Pedram</creatorcontrib><creatorcontrib>Lotan, Tamara L</creatorcontrib><title>GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms</title><title>The Journal of pathology</title><addtitle>J Pathol</addtitle><description>GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2‐associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR–Cas9 genome editing as well as in a mouse model of Tsc2 inactivation‐driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3‐ or TFEB‐driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low‐grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE‐ and mTORC1‐dependent fashion. Renal tumors in Tsc2+/− A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration‐associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration‐associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB‐transcriptional targets as diagnostic markers. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</description><subject>Angiomyolipoma</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>CRISPR</subject><subject>Eye Proteins</subject><subject>Female</subject><subject>Genome editing</subject><subject>Genomes</subject><subject>GPNMB</subject><subject>Humans</subject><subject>Image processing</subject><subject>Immunohistochemistry</subject><subject>Kidney cancer</subject><subject>Kidney Neoplasms - pathology</subject><subject>Kidneys</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukocytes (eosinophilic)</subject><subject>Male</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Mice</subject><subject>Microphthalmia</subject><subject>Microphthalmos - genetics</subject><subject>Original</subject><subject>Perivascular Epithelioid Cell Neoplasms - genetics</subject><subject>Renal cell carcinoma</subject><subject>TFE3</subject><subject>TFEB</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - genetics</subject><subject>Transcription</subject><subject>Transcription Factors - genetics</subject><subject>translocation renal cell carcinoma</subject><subject>Translocation, Genetic</subject><subject>TSC1/2</subject><subject>Tuberous Sclerosis</subject><subject>Tuberous Sclerosis Complex 1</subject><subject>Tuberous Sclerosis Complex 2</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0022-3417</issn><issn>1096-9896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1u1DAUhS0EokNhwQugSGxgkY5_EjveIJURtEgtrSCsLSe-oR45cWpnCrPjEXjGPkmdTlsBEqu7uJ8-naOD0EuCDwjGdDnq6eKgrET5CC0IljyXleSP0SL9aM4KIvbQsxjXGGMpy_Ip2mMlFlQWYoHWR-efT99n8HMMEKP1Q2YNDJPtLMSs_roiS7rs67Mv179-6xh9a_UEJtODyU5tnXW6t26bTUEP0flWT0mQSBPsFQxZgEG7bAA_Oh37-Bw96bSL8OLu7qNvHz_Uq-P85Ozo0-rwJG-LgpU5qZrSNITqFgpDOZeYy65hQjOmMQchGk6ZkKQwGAsMGhsGppMGAAvOJLB99G7nHTdND6ZNdYJ2agy212GrvLbq789gL9R3f6UkI1hUJAne3AmCv9xAnFRvYwvO6dRlExXllBaiomRGX_-Drv0mpNozVco0QFHSRL3dUW3wMQboHsIQrOYF1bygmhdM7Ks_0z-Q95MlYLkDflgH2_-b1PlhfXyrvAG_76iw</recordid><startdate>202206</startdate><enddate>202206</enddate><creator>Salles, Daniela C</creator><creator>Asrani, Kaushal</creator><creator>Woo, Juhyung</creator><creator>Vidotto, Thiago</creator><creator>Liu, Hans B</creator><creator>Vidal, Igor</creator><creator>Matoso, Andres</creator><creator>Netto, George J</creator><creator>Argani, Pedram</creator><creator>Lotan, Tamara L</creator><general>John Wiley & Sons, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0494-9067</orcidid><orcidid>https://orcid.org/0000-0003-1904-185X</orcidid></search><sort><creationdate>202206</creationdate><title>GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms</title><author>Salles, Daniela C ; Asrani, Kaushal ; Woo, Juhyung ; Vidotto, Thiago ; Liu, Hans B ; Vidal, Igor ; Matoso, Andres ; Netto, George J ; Argani, Pedram ; Lotan, Tamara L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4435-18b5db12ace4d2669069fb37a33a06e77b6237914d0070ea0d3edf9dee07639e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Angiomyolipoma</topic><topic>Animals</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>CRISPR</topic><topic>Eye Proteins</topic><topic>Female</topic><topic>Genome editing</topic><topic>Genomes</topic><topic>GPNMB</topic><topic>Humans</topic><topic>Image processing</topic><topic>Immunohistochemistry</topic><topic>Kidney cancer</topic><topic>Kidney Neoplasms - pathology</topic><topic>Kidneys</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukocytes (eosinophilic)</topic><topic>Male</topic><topic>Mechanistic Target of Rapamycin Complex 1</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Mice</topic><topic>Microphthalmia</topic><topic>Microphthalmos - genetics</topic><topic>Original</topic><topic>Perivascular Epithelioid Cell Neoplasms - genetics</topic><topic>Renal cell carcinoma</topic><topic>TFE3</topic><topic>TFEB</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - genetics</topic><topic>Transcription</topic><topic>Transcription Factors - genetics</topic><topic>translocation renal cell carcinoma</topic><topic>Translocation, Genetic</topic><topic>TSC1/2</topic><topic>Tuberous Sclerosis</topic><topic>Tuberous Sclerosis Complex 1</topic><topic>Tuberous Sclerosis Complex 2</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salles, Daniela C</creatorcontrib><creatorcontrib>Asrani, Kaushal</creatorcontrib><creatorcontrib>Woo, Juhyung</creatorcontrib><creatorcontrib>Vidotto, Thiago</creatorcontrib><creatorcontrib>Liu, Hans B</creatorcontrib><creatorcontrib>Vidal, Igor</creatorcontrib><creatorcontrib>Matoso, Andres</creatorcontrib><creatorcontrib>Netto, George J</creatorcontrib><creatorcontrib>Argani, Pedram</creatorcontrib><creatorcontrib>Lotan, Tamara L</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salles, Daniela C</au><au>Asrani, Kaushal</au><au>Woo, Juhyung</au><au>Vidotto, Thiago</au><au>Liu, Hans B</au><au>Vidal, Igor</au><au>Matoso, Andres</au><au>Netto, George J</au><au>Argani, Pedram</au><au>Lotan, Tamara L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms</atitle><jtitle>The Journal of pathology</jtitle><addtitle>J Pathol</addtitle><date>2022-06</date><risdate>2022</risdate><volume>257</volume><issue>2</issue><spage>158</spage><epage>171</epage><pages>158-171</pages><issn>0022-3417</issn><eissn>1096-9896</eissn><abstract>GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2‐associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR–Cas9 genome editing as well as in a mouse model of Tsc2 inactivation‐driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3‐ or TFEB‐driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low‐grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE‐ and mTORC1‐dependent fashion. Renal tumors in Tsc2+/− A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration‐associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration‐associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB‐transcriptional targets as diagnostic markers. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>35072947</pmid><doi>10.1002/path.5875</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-0494-9067</orcidid><orcidid>https://orcid.org/0000-0003-1904-185X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-3417 |
| ispartof | The Journal of pathology, 2022-06, Vol.257 (2), p.158-171 |
| issn | 0022-3417 1096-9896 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9310781 |
| source | Wiley Online Library - AutoHoldings Journals; MEDLINE |
| subjects | Angiomyolipoma Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics Biomarkers, Tumor - analysis Biomarkers, Tumor - genetics Carcinoma, Renal Cell - pathology CRISPR Eye Proteins Female Genome editing Genomes GPNMB Humans Image processing Immunohistochemistry Kidney cancer Kidney Neoplasms - pathology Kidneys Leukemia, Myeloid, Acute - genetics Leukocytes (eosinophilic) Male Mechanistic Target of Rapamycin Complex 1 Membrane Glycoproteins - genetics Mice Microphthalmia Microphthalmos - genetics Original Perivascular Epithelioid Cell Neoplasms - genetics Renal cell carcinoma TFE3 TFEB TOR protein TOR Serine-Threonine Kinases - genetics Transcription Transcription Factors - genetics translocation renal cell carcinoma Translocation, Genetic TSC1/2 Tuberous Sclerosis Tuberous Sclerosis Complex 1 Tuberous Sclerosis Complex 2 Tumorigenesis Tumors |
| title | GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T03%3A09%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=GPNMB%20expression%20identifies%20TSC1/2/mTOR%E2%80%90associated%20and%20MiT%20family%20translocation%E2%80%90driven%20renal%20neoplasms&rft.jtitle=The%20Journal%20of%20pathology&rft.au=Salles,%20Daniela%20C&rft.date=2022-06&rft.volume=257&rft.issue=2&rft.spage=158&rft.epage=171&rft.pages=158-171&rft.issn=0022-3417&rft.eissn=1096-9896&rft_id=info:doi/10.1002/path.5875&rft_dat=%3Cproquest_pubme%3E2659002452%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2659002452&rft_id=info:pmid/35072947&rfr_iscdi=true |