Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research Samples were submitted to the New York Genome Center (NYGC) for nucleic acid extraction as well as RNA-sequencing (RNA-Seq). 6 Sglt2-Cre; ASPSCR1-TFE3 LSL/+ mice were used for RNA-Seq studies encompassing 22 samples: 11 kidney tumors; 4 retro-orbital tumors; 3 brain tumors as well as 4 non-transformed kidney samples. In addition, RNA isolation and RNA-Seq were performed on 6 normal kidney samples from 3 Sglt2-Cre control mice. Kidney samples from 5 Pax8-Cre; ASPSCR1-TFE3 LSL/+ fetus and 3 Pax8-Cre or ASPSCR1-TFE3 LSL/+ age-matched controls were submitted for RNA-Seq. All samples were from formalin-fixed and paraffin-embedded (FFPE) tissues.