Recurrent TRIO fusion in non-translocation-related sarcomas

Purpose:Despite various differences, non-translocation-related sarcomas (comprising UPS, LMS, MFS e.g.) are unified by their complex genetics. Extensive analysis of the tumor genome using molecular cytogenetic approaches showed many chromosomal gains, losses and translocations per cell. Genomic quantitative alterations and expression variations have been extensively studied by adapted high-throughput approaches, yet translocations still remained unscreened. We therefore analyzed 117 non-translocation-related sarcomas by RNA sequencing to identify fusion genes. Experimental Design:We performed RNA sequencing and applied a bioinformatics pipeline dedicated to detection of fusion transcripts. RT-PCR and Sanger sequencing were then applied to validate predictions and to search for recurrence and specificity. Results:Among the 6,772 predicted fusion genes, 420 were in-frame. One recurrent rearrangement, consistently involving TRIO with various partners, was identified in 5.1% of cases. TRIO translocations are either intra-chromosomal with TERT or inter-chromosomal with LINC01504 or ZNF558. Our results suggest that all translocations lead to a truncated TRIO protein either directly or indirectly by alternative splicing. TRIO rearrangement is associated with a modified transcriptomic program to immunity/inflammation, proliferation and migration and an increase in proliferation. Conclusions:TRIO fusions have been identified in four different sarcoma histotypes likely meaning that they are not related to a primary oncogenic event but rather to a secondary one implicated in tumor progression. Moreover, they appear to be specific to non-translocation-related sarcomas since no such rearrangement was identified in sarcomas with simple genetics. More cases could lead to a significant association of these fusions to a specific clinical behavior.

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