<i>MYC</i> Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification

Abstract

The amplified <i>MYCN</i> gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member <i>MYC</i> 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 <i>MYC</i> activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the <i>MYC</i> gene locus. The clinical outcome for patients with high levels of <i>MYC</i> expression is virtually identical to that of patients with amplification of the <i>MYCN</i> gene, a known high-risk feature of this disease. Together, these findings establish <i>MYC</i> as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.<b>Significance:</b> Amplification of the <i>MYCN</i> oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that <i>MYC</i> 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. <i>Cancer Discov; 8(3); 320-35. ©2017 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 253</i>.