GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms

J Pathol. 2022 Jun;257(2):158-171. doi: 10.1002/path.5875. Epub 2022 Mar 29.


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.

Keywords: GPNMB; TFE3; TFEB; TSC1/2; angiomyolipoma; renal cell carcinoma; translocation renal cell carcinoma.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics
  • Carcinoma, Renal Cell* / pathology
  • Eye Proteins
  • Female
  • Humans
  • Kidney Neoplasms* / pathology
  • Leukemia, Myeloid, Acute* / genetics
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Glycoproteins / genetics
  • Mice
  • Microphthalmos* / genetics
  • Perivascular Epithelioid Cell Neoplasms* / genetics
  • TOR Serine-Threonine Kinases / genetics
  • Transcription Factors / genetics
  • Translocation, Genetic
  • Tuberous Sclerosis


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Biomarkers, Tumor
  • Eye Proteins
  • GPNMB protein, human
  • Gpnmb protein, mouse
  • Membrane Glycoproteins
  • Transcription Factors
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases

Supplementary concepts

  • Tuberous Sclerosis 2