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GPNMB expression identifies TSC1 /2/ mTOR ‐associated and MiT family translocation‐driven renal neoplasms
Author(s) -
Salles Daniela C,
Asrani Kaushal,
Woo Juhyung,
Vidotto Thiago,
Liu Hans B,
Vidal Igor,
Matoso Andres,
Netto George J,
Argani Pedram,
Lotan Tamara L
Publication year - 2022
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5875
Subject(s) - tfe3 , tsc1 , tfeb , tuberous sclerosis , angiomyolipoma , clear cell , cancer research , clear cell renal cell carcinoma , chromophobe cell , renal cell carcinoma , pathology , biology , immunohistochemistry , podocyte , perivascular epithelioid cell , downregulation and upregulation , kidney , pi3k/akt/mtor pathway , medicine , microbiology and biotechnology , endocrinology , gene expression , biogenesis , biochemistry , signal transduction , promoter , epithelioid cell , gene , proteinuria
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.