Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

被引:125
作者
Gruenewald, Thomas G. P. [1 ,2 ]
Bernard, Virginie [3 ]
Gilardi-Hebenstreit, Pascale [4 ]
Raynal, Virginie [1 ,2 ,3 ]
Surdez, Didier [1 ,2 ]
Aynaud, Marie-Ming [1 ,2 ]
Mirabeau, Olivier [1 ,2 ]
Cidre-Aranaz, Florencia [5 ]
Tirode, Franck [1 ,2 ]
Zaidi, Sakina [1 ,2 ]
Perot, Gaelle [6 ]
Jonker, Anneliene H. [1 ,2 ]
Lucchesi, Carlo [1 ,2 ]
Le Deley, Marie-Cecile [7 ]
Oberlin, Odile [8 ]
Marec-Berard, Perrine [9 ]
Veron, Amelie S. [10 ]
Reynaud, Stephanie [11 ]
Lapouble, Eve [11 ]
Boeva, Valentina [12 ,13 ]
Frio, Thomas Rio [3 ]
Alonso, Javier [5 ]
Bhatia, Smita [14 ]
Pierron, Gaelle [11 ]
Cancel-Tassin, Geraldine [15 ]
Cussenot, Olivier [15 ]
Cox, David G. [10 ]
Morton, Lindsay M. [16 ]
Machiela, Mitchell J. [16 ]
Chanock, Stephen J. [16 ]
Charnay, Patrick [4 ]
Delattre, Olivier [1 ,2 ,3 ,11 ]
机构
[1] PSL Res Univ, Inst Curie, Genet & Biol Canc Unit, Paris, France
[2] Inst Curie, Res Ctr, INSERM, U830, Paris, France
[3] Inst Curie, Res Ctr, Inst Curie Genom Excellence ICGex Platform, Paris, France
[4] Ecole Normale Super, CNRS, INSERM, Inst Biol ENS IBENS,U1024,UMR8197, Paris, France
[5] Inst Salud Carlos III, Inst Invest Enfermedades Raras, Madrid, Spain
[6] INSERM, Biol Sarcomas U916, Inst Bergonie, Bordeaux, France
[7] Inst Gustave Roussy, Dept Epidemiol & Biostat, Villejuif, France
[8] Inst Gustave Roussy, Dept Pediat, Villejuif, France
[9] Univ Lyon, Leon Berard Canc Ctr, Inst Pediat Hematol & Oncol, Lyon, France
[10] Canc Res Ctr Lyon, Leon Berard Canc Ctr, U1052, INSERM, Lyon, France
[11] Inst Curie Ctr Hosp, UGS, Paris, France
[12] Inst Curie, Res Ctr, INSERM, Bioinformat Biostat Epidemiol & Computat Syst Bio, Paris, France
[13] Mines ParisTech, Fontainebleau, France
[14] Univ Alabama Birmingham, Sch Med, Inst Canc Outcomes & Survivorship, Birmingham, AL USA
[15] Univ Paris 06, Hop Tenon, Ctr Rech Pathol Prostat CeRePP, Lab Urol,Res Team 2, Paris, France
[16] NCI, DCEG, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
GENOME-WIDE ASSOCIATION; TRANSCRIPTION; EXPRESSION; CHROMATIN; REVEALS; COMMON; KROX20; RISK; VISUALIZATION; GENERATION;
D O I
10.1038/ng.3363
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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(1-3). A recent genome-wide association study(4) 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.
引用
收藏
页码:1073 / +
页数:9
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