TY - JOUR
T1 - Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite
AU - Grünewald, Thomas G.P.
AU - Bernard, Virginie
AU - Gilardi-Hebenstreit, Pascale
AU - Raynal, Virginie
AU - Surdez, Didier
AU - Aynaud, Marie Ming
AU - Mirabeau, Olivier
AU - Cidre-Aranaz, Florencia
AU - Tirode, Franck
AU - Zaidi, Sakina
AU - Perot, Gaëlle
AU - Jonker, Anneliene H.
AU - Lucchesi, Carlo
AU - Le Deley, Marie Cécile
AU - Oberlin, Odile
AU - Marec-Bérard, Perrine
AU - Véron, Amélie S.
AU - Reynaud, Stephanie
AU - Lapouble, Eve
AU - Boeva, Valentina
AU - Frio, Thomas Rio
AU - Alonso, Javier
AU - Bhatia, Smita
AU - Pierron, Gaëlle
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Cox, David G.
AU - Morton, Lindsay M.
AU - MacHiela, Mitchell J.
AU - Chanock, Stephen J.
AU - Charnay, Patrick
AU - Delattre, Olivier
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/8/27
Y1 - 2015/8/27
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.3363
DO - 10.1038/ng.3363
M3 - Article
C2 - 26214589
AN - SCOPUS:84940568773
SN - 1061-4036
VL - 47
SP - 1073
EP - 1078
JO - Nature genetics
JF - Nature genetics
IS - 9
ER -