Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma

Abstract

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.

Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents

“…Furthermore, TFE3 could promote the endolysosomal deprivation reaction by inducing the expression of autolysosomal genes [ 33 , 34 ]. Recently, Zeng et al demonstrated that lysosomal and autophagy pathways were significantly upregulated in TFE3-tRCC [ 35 ]. Previous studies indicated that elevated doses of crizotinib can induce autophagy in alveolar rhabdomyosarcoma cells [ 36 ] and that autophagy is required for crizotinib-induced apoptosis in MET-amplified gastric cancer cells [ 23 ].…”

MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights

“…Adult patients most often present with advanced and aggressive metastatic disease, with a median overall survival after diagnosis of approximately 18 months [ 18 ]. Some fusion partners such as ASPL/ASPSCR1-TFE3 fusion have been associated with having worse outcomes [ 19 , 20 ].…”

“…Taking advantage of recent advances in the prognostic significance of certain fusion partners, this powerful technique could become the future gold standard for diagnosis. Whole exome sequencing can also be used to identify fusion partners with the advantage of providing other interesting information regarding copy number variation or variation in other genes that may impact patient outcomes or predict treatment efficacy [ 20 , 30 ].…”

“…Initially described in 1986, XP11 tRCC is defined by the fusion between the TFE3 transcription factor gene (locus Xp11.2) and different partner genes. Approximately 20 distinct partners have been described to date [ 10 , 20 ] ( Table 3 ). The most common partners involved in TFE3-tRCC are PRCC (papillary renal cell carcinoma) with t(X;1)(p11.2;q21.2), ASPSCR1 ( ASPL) (alveolar soft part sarcoma locus) with the t(X;17)(p11.2;q25) and SFPQ (splicing factor proline- and glutamine-rich protein) with t(X;1)(p11.2;p34) [ 7 , 20 , 31 ].…”

“…Approximately 20 distinct partners have been described to date [ 10 , 20 ] ( Table 3 ). The most common partners involved in TFE3-tRCC are PRCC (papillary renal cell carcinoma) with t(X;1)(p11.2;q21.2), ASPSCR1 ( ASPL) (alveolar soft part sarcoma locus) with the t(X;17)(p11.2;q25) and SFPQ (splicing factor proline- and glutamine-rich protein) with t(X;1)(p11.2;p34) [ 7 , 20 , 31 ]. Less recurrent TFE3 fusion partners include NONO (non-POU domain containing octamer binding) resulting from inv(X) (p11.2q12) [ 32 ], CLTC (clathrin heavy chain) resulting from t(X; 17) (p11.2; q23) [ 33 ] and RBM10 (RNA binding motif protein 10) resulting from inv(X) (p11.2p11.23) [ 34 ].…”