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

Abstract

The amplified gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member 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 activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the gene locus. The clinical outcome for patients with high levels of expression is virtually identical to that of patients with amplification of the gene, a known high-risk feature of this disease. Together, these findings establish as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. Amplification of the oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that 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. .

Nanopore sequencing of DNA concatemers reveals higher-order features of chromatin structure

“…Previous work in constitutional genetics has linked the pres-ence of inherited non-coding DNA variants, such as CTCF mutations 10 or larger structural variants 11,12 , to human limb malformations through chromatin re-structuring 10 . In cancer, complex somatic genomic rearrangements can create neo-TADs 11,13 or hijack enhancers to activate oncogenes [14][15][16][17][18] .…”

Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

“…In addition, alignment based approaches offer single base pair resolution and genome-wide coverage in the case of WGS. Recent studies using alignment based detection of SVs from WGS profiles from primary neuroblastomas revealed structural rearrangements as key oncogenic drivers mediating focal enhancer amplification or enhancer hijacking, influencing telomere maintenance through activation of telomerase reverse transcriptase gene (TERT) 24,27,28 or by deregulating the MYC oncogene 29 . Despite the demonstrated importance of somatic CNVs and other SVs in neuroblastoma, studies systematically integrating CNV analysis and alignment based approaches are lacking; hence the global landscape and mechanisms of pathogenicity of many of these events remain poorly understood.…”

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

“…To evaluate Sulfopin's effects on Myc-driven cancers, we turned to a zebrafish model of neuroblastoma [90][91][92] , a pediatric malignancy derived from the peripheral sympathetic nervous system (PSNS) 93 . During the development of normal zebrafish embryos, neural crest-derived PSNS neuroblasts form the primordial superior cervical ganglia (SCG) and intrarenal gland (IRG) at the age of 3 to 7 days post fertilization (dpf), can be visualized using the dβh:EGFP fluorescent reporter 91 (Fig.…”

“…These neuroblast hyperplasia rapidly progress into fully transformed tumors that faithfully resemble human high-risk neuroblastoma [90][91][92] . When Sulfopin was added to the fish water containing Tg(dβh:MYCN;dβh:EGFP) zebrafish (at concentrations of 25-100 µM), the neuroblastoma-initiating hyperplasia was significantly suppressed and fully transformed neuroblastoma did not develop over the treatment period (Fig.…”