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Article Abstract
Objectives: Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transcriptional target of MiTF/TFE3. Prior studies have shown that immunohistochemistry for GPNMB is a sensitive screening tool for renal cell carcinomas with alterations of TSC1/TSC2/MTOR, TFE3, and TFEB genes, as well as alveolar soft part sarcomas (ASPS) and perivascular epithelioid cell neoplasms (PEComas). However, GPNMB expression has not been systematically evaluated in a diverse group of molecularly confirmed, TFE3-rearranged mesenchymal tumors.
Methods: Our archive was interrogated for TFE3-rearranged non-renal neoplasms previously assessed with our RNA NGS panel. For each case, a whole-slide section was immunostained for GPNMB, and quantified using H-scores. The methylation profiles of the included tumor types were retrieved from our database.
Results: Thirteen TFE3-rearranged tumors were identified, including 6 ossifying fibromyxoid tumors (OFMTs) (PHF1::TFE3), 3 PEComas/PEComa-like neoplasms (ASPSCR1::TFE3, DVL2::TFE3, and PRCC::TFE3, one case each), 2 YAP1::TFE3-rearranged hemangioendotheliomas, one ASPS (ASPSCR1::TFE3), and one unclassified CBX4::TFE3-rearranged sarcoma. Tumors harboring ASPSCR1, PRCC, YAP1, and DVL2 as the fusion partner had a mean H-score of 300, 300, 290 and 280, respectively. All 6 PHF1::TFE3-rearranged OFMTs and the CBX4::TFE3-rearranged sarcoma were GPNMB-negative, despite having similar TFE3 breakpoints to the positive cases (exon 6-7). PHF1::TFE3-rearranged OFMT showed relative hypermethylation of the GPNMB promoter locus cg02203656 compared to ASPS (p = 0.027).
Conclusions: Although study of additional cases is necessary, these findings suggest that the downstream effects of TFE3-rearrangement are different in PHF1::TFE3-rearranged OFMTs, compared to other known TFE3-rearranged neoplasms. TFE3-rearranged OFMTs are epigenetically distinct, implying that the impact of TFE3-rearrangement may be lineage-dependent.
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| http://dx.doi.org/10.1016/j.humpath.2025.105768 | DOI Listing |
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