Abstract 3527: Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma

Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a newly defined subset of RCC, which have chromosomal translocations involving the TFE3 transcription factor at Xp11.2. All translocations seen in Xp11.2 tRCC, including PRCC-TFE3, PSF-TFE3, ASPL-TFE3, CTLC-TFE3 and NONO-TFE3 produce chimeric TFE3 genes, which encode fusion TFE3 proteins retaining the basic helix-loop-helix leucine zipper (bHLH-Zip) structure for DNA binding, suggesting that these fusion TFE3 proteins function as oncogenic transcription factors. To clarify the molecular mechanism for Xp11.2 tRCC development, we have established cell lines, which express fusion TFE3 proteins (NONO-TFE3, PRCC-TFE3, PSF-TFE3) in a doxycycline dependent manner. Genes upregulated universally in all fusion TFE3 cell lines upon doxycycline addition were identified. In addition, we have generated an Xp11.2 translocation RCC mouse model, in which a floxed Neomycin cassette followed by a PRCC-TFE3 cDNA is inserted in the Rosa26 locus. By crossing these mice with cadherin 16-Cre transgenic mice, we can induce kidney specific PRCC-TFE3 expression resulting in RCC development. We will report and discuss the role of fusion TFE3 target genes in our mouse model and in clinical samples of Xp11.2 tRCC. Funded in part by FNLCR Contract HHSN261200800001E to LSS. Citation Format: Masaya Baba, Ying Huang, Takanobu Motoshima, Hisashi Hasumi, Yukiko Hasumi, Mitsuko Furuya, Yoji Nagashima, Masahiro Yao, Yuichi Oike, Tomomi Kamba, Laura S. Schmidt, W. Marston Linehan. Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3527. doi:10.1158/1538-7445.AM2017-3527