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Nat Genet. 2015 Sep;47(9):1073-8. doi: 10.1038/ng.3363. Epub 2015 Jul 27.

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

Author information

1
Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.
2
INSERM U830, Institut Curie Research Center, Paris, France.
3
Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France.
4
École Normale Supérieure (ENS), Institut de Biologie de l'ENS (IBENS), INSERM U1024, CNRS UMR8197, Paris, France.
5
Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
6
INSERM U916 Biology of Sarcomas, Institut Bergonié, Bordeaux, France.
7
Département d'Epidémiologie et de Biostatistiques, Institut Gustave Roussy, Villejuif, France.
8
Département de Pédiatrie, Institut Gustave Roussy, Villejuif, France.
9
Institute for Pediatric Hematology and Oncology, Leon-Bérard Cancer Center, University of Lyon, Lyon, France.
10
INSERM U1052, Léon-Bérard Cancer Centre, Cancer Research Center of Lyon, Lyon, France.
11
Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France.
12
INSERM U900, Bioinformatics, Biostatistics, Epidemiology and Computational Systems Biology of Cancer, Institut Curie Research Center, Paris, France.
13
Mines ParisTech, Fontainebleau, France.
14
Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama, Birmingham, Alabama, USA.
15
Centre de Recherche sur les Pathologies Prostatiques (CeRePP)-Laboratory for Urology, Research Team 2, UPMC, Hôpital Tenon, Paris, France.
16
Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, Maryland, USA.

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.

PMID:
26214589
PMCID:
PMC4591073
DOI:
10.1038/ng.3363
[Indexed for MEDLINE]
Free PMC Article

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