From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

Abstract

Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.

The fork restart factor PHF6 interacts with RRM2 and binds to H3K56ac marked nascent DNA

“…These observations converge towards a putative tumor promoting role for PHF6 in neuroblastoma. It is known that high-risk neuroblastoma genomes, while having a low mutational load are marked by highly recurrent DNA copy number alterations, including 2p and 17q gains 37 . However, no recurrent gains encompassing the PHF6 locus on the X-chromosome have been identified in high-risk neuroblastoma patient data 38 .…”

RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

“…In contrast to the low mutational burden, DNA copy number changes are highly recurrent with 2p and 17q gains occurring in both MYCN-amplified and nonamplified high-risk cases, while 1p and 11q deletions are predominantly found in MYCN-amplified and MYCN-nonamplified high-risk cases, respectively. We and others previously showed that focal gains and amplifications can highlight candidate genes implicated in neuroblastoma initiation and/or maintenance, potentially expanding the current number of available druggable targets (3,4). Recent whole-genome sequencing efforts have uncovered recurrent complex rearrangements, including chromothripsis affecting the chromosome 2 short arm.…”

Gene utility recapitulates chromosomal aberrancies in advanced stage neuroblastoma

“…However, the biological basis for the association of MYCN amplification with those specific chromosomal aberrancies, such as 1p loss or 17q gain, remains enigmatic. Although loss of ARID1A (located in the 1p36 deleted region [15] ), or overexpression of BIRC5 (located in the commonly gained 17q segment [16] , [17] have been recently shown to synergize with MYCN to promote NB tumorigenesis [18] , [19] , limited number of genes within these altered chromosomal regions were found to be bona fide tumor suppressors or oncogenes or to cooperate with MYCN to contribute to NB pathogenesis. Hence, gain or loss-of-function of individual oncogenes or tumor suppressor genes cannot fully address the association of unique patterns of segmental chromosomal aberrancies to the advanced stage NB.…”