title: Recurrent TRIO Fusion in Nontranslocation-Related Sarcomas.
abstract: OBJECTIVE
  Despite various differences, nontranslocation-related sarcomas (e.g., comprising undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxofibrosarcoma) 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 nontranslocation-related sarcomas by RNA sequencing to identify fusion genes.
  
  
  METHODS
  We performed RNA sequencing and applied a bioinformatics pipeline dedicated to the 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 intrachromosomal with TERT or interchromosomal with LINC01504 or ZNF558 Our results suggest that all translocations led 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 nontranslocation-related sarcomas, as 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. Clin Cancer Res; 23(3); 857-67. ©2016 AACR.
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Delespaul
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Tom
authors.initials: T
authors.lastname: Lesluyes
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|Department of Pathology, Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pérot
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Brulard
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Lartigue
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Baud
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Lagarde
authors.affiliation: Department of Pathology, University Cancer institute Toulouse-Oncopole, Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Guellec
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|Department of Pathology, Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Neuville
authors.affiliation: Department of Pathology, Gustave Roussy Institute, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Terrier
authors.affiliation: Department of Pathology, Léon Bérard Center, Lyon, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Vince-Ranchère
authors.affiliation: Centre de Recherche en Biologie Cellulaire de Montpellier, CRBM, CNRS-UMR 5237, University of Montpellier, Montpellier, France.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Centre de Recherche en Biologie Cellulaire de Montpellier, CRBM, CNRS-UMR 5237, University of Montpellier, Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Debant
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France.|University of Bordeaux, Bordeaux, France.|Department of Pathology, Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: Inserm U916, Bergonié Cancer Institute, Bordeaux, France. F.chibon@bordeaux.unicancer.fr.|Department of Pathology, Bergonié Cancer Institute, Bordeaux, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chibon
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012509:Sarcoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017423:Sequence Analysis, RNA; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C584091:ZNF558 protein, human; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human; C509186:TERT protein, human; D019098:Telomerase