Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.
Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.
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DOI：
10.1038/ng.3363
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发表时间：
2015-09
期刊：
影响因子：
30.8
通讯作者：
Delattre O
中科院分区：
文献类型：
--
作者：
Grünewald TG;Bernard V;Gilardi-Hebenstreit P;Raynal V;Surdez D;Aynaud MM;Mirabeau O;Cidre-Aranaz F;Tirode F;Zaidi S;Perot G;Jonker AH;Lucchesi C;Le Deley MC;Oberlin O;Marec-Bérard P;Véron AS;Reynaud S;Lapouble E;Boeva V;Rio Frio T;Alonso J;Bhatia S;Pierron G;Cancel-Tassin G;Cussenot O;Cox DG;Morton LM;Machiela MJ;Chanock SJ;Charnay P;Delattre O
破译体细胞突变和生殖系易感性变异协同促进癌症的方式具有挑战性。尤文肉瘤的特征是EWSR 1和ETS基因家族成员之间的融合，通常是EWSR 1-FLI 1，导致在GGAA基序处结合DNA的致癌转录因子的产生。最近的一项全基因组关联研究确定了EGR 2附近的易感性变体。我们发现EGR 2基因敲低抑制体外尤文肉瘤的增殖、克隆形成和球状体生长，并诱导尤文肉瘤异种移植物消退。在受影响的受试者和对照者中对EGR 2基因座进行的靶向种系深度测序显示了291个尤文相关的SNP。在rs79965208处，A风险等位基因通过将间隔的GGAT基序转化为GGAA基序来连接相邻的GGAA重复，从而增加连续GGAA基序的数量，并因此增加该序列的EWSR 1-FLI 1依赖性增强子活性，具有活性调节元件的表观遗传特征。EWSR 1-FLI 1优先与A风险等位基因结合，这增加了整体和等位基因特异性EGR 2表达。总的来说，我们的研究结果建立了显性癌基因和调节尤文肉瘤形成主要驱动因素的易感性变体之间的合作。
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 revealed 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.