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Chimeric oncogene regulates the EGR2 sarcoma susceptibility gene via a GGAA-microsatellite

Thomas Grünewald 1 Virginie Bernard 2 Pascale Gilardi-Hebenstreit 3 Virginie Raynal 1 Didier Surdez 1 Marie-Ming Aynaud 1 Florencia Cidre-Aranaz 4 Olivier Mirabeau 1 Franck Tirode 1 Gaëlle Pérot 5 Anneliene Jonker 1 Carlo Lucchesi 1 Marie-Cécile Le Deley 6 Odile Oberlin 7 Perrine Marec-Bérard 8 Amélie Véron 9 Stéphanie Reynaud 10 Eve Lapouble 10 Valentina Boeva 11 Thomas Rio Frio 2 Javier Alonso 4 Gaëlle Pierron 12 Geraldine Cancel-Tassin 13 Olivier Cussenot 13 David Cox 9 Stephen Chanock 14 Patrick Charnay 3 Olivier Delattre 1, 2, 10, *
* Corresponding author
1 U830 - Unité de génétique et biologie des cancers
2 Genomics of Excellence (ICGex) Platform
3 IBENS - Institut de biologie de l'ENS Paris (UMR 8197/1024)
4 Instituto de Investigacion de Enfermedades Raras [Madrid, Spain]
5 VINCO - Validation et identification de nouvelles cibles en oncologie
6 CESP - Centre de recherche en épidémiologie et santé des populations
7 Département de Pédiatrie
8 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
9 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
10 Unité de Génétique Somatique [Institut Curie, Paris]
11 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
12 Unité de Génétique Somatique
13 CHU Tenon [APHP]
14 Division of Cancer Epidemiology and Genetics
Abstract : Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis
Keywords : germline susceptibility Ewing sarcoma EWSR1-FLI1 GGAA- microsatellite EGR2
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INSERM | HCL | CESP | BERGONIE | CURIE | UVSQ | FNCLCC | UNIV-LYON1 | ENSMP | UNIV-PARIS5 | ENS-PARIS | ENSMP_CBIO | CRCL | USPC | CNRS | UDL | INSTITUT-TELECOM | PARISTECH | IGR | UNIV-PARIS | PSL | SORBONNE-UNIVERSITE | SU-TI

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Thomas Grünewald, Virginie Bernard, Pascale Gilardi-Hebenstreit, Virginie Raynal, Didier Surdez, et al.. Chimeric oncogene regulates the EGR2 sarcoma susceptibility gene via a GGAA-microsatellite. Nature Genetics, Nature Publishing Group, 2015, 47 (9), pp.1073-1078. ⟨10.1038/ng.3363⟩. ⟨inserm-02440399⟩

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