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MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification
Cancer Discovery ( IF 29.7 ) Pub Date : 2018-03-01 , DOI: 10.1158/2159-8290.cd-17-0993
Mark W Zimmerman 1 , Yu Liu 2 , Shuning He 1 , Adam D Durbin 1 , Brian J Abraham 3 , John Easton 2 , Ying Shao 2 , Beisi Xu 2 , Shizhen Zhu 4 , Xiaoling Zhang 4 , Zhaodong Li 1 , Nina Weichert-Leahey 1 , Richard A Young 3, 5 , Jinghui Zhang 2 , A Thomas Look 1
Affiliation  

The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.

Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 253



中文翻译:


MYC 驱动高风险儿童神经母细胞瘤的一个子集,并通过增强子劫持和局灶增强子放大等机制激活



扩增的MYCN基因在大约 20% 的高危儿科神经母细胞瘤中充当致癌驱动因素。在这里,我们表明,家族成员MYC在高风险神经母细胞瘤病例的一个单独子集中(~10%)中是一个有效的转化基因,基于(i)其通过局部增强子扩增或基因组重排导致增强子劫持而上调,以及(ii) 其在转基因动物模型中转化神经母细胞瘤前体细胞的能力。与致癌MYC激活相关的异常调控元件包括局灶性扩增的远端增强子和高活性增强子从其他基因易位到包含MYC基因座的拓扑关联域内。 MYC表达水平高的患者的临床结果实际上与MYCN基因扩增的患者相同,而 MYCN 基因扩增是该疾病的已知高风险特征。总之,这些发现证实MYC是临床上有意义的高危儿童神经母细胞瘤组中的真正癌基因。


意义: MYCN癌基因的扩增是高危儿科神经母细胞瘤的公认标志。在这里,我们证明MYC也通过远端增强子的局灶性扩增或染色体易位介导的增强子劫持在神经母细胞瘤病例的独特子集中被激活为强癌基因。癌症发现; 8(3); 320–35。 ©2017 AACR。


这篇文章在本期特稿中重点介绍,第 17 页。第253章

更新日期:2018-03-02
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