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From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma
Bieke Decaesteker1, Kaat Durinck1, Nadine Van Roy1
1Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium.
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.
Insights
Neuroblastoma, a leading cause of childhood cancer deaths, is often driven by DNA copy number aberrations. Identifying genes within these regions offers new therapeutic targets for high-risk patients.
Area of Science:
- Pediatric oncology
- Cancer genomics
- Molecular biology
Background:
- Neuroblastoma is a significant cause of childhood cancer mortality worldwide.
- High-risk neuroblastoma patients face poor survival and therapy-related side effects.
- Despite low mutation rates, DNA copy number aberrations are common and linked to poor prognosis.
Purpose of the Study:
- To review recurrent DNA copy number aberrations in neuroblastoma.
- To identify genes affected by these aberrations with established roles in neuroblastoma.
- To explore potential therapeutic targets based on copy-number driven gene dependencies.
Main Methods:
- Review of current literature on neuroblastoma genomics.
- Analysis of genes within recurrently amplified or deleted chromosomal regions.
- Investigation of gene networks regulating MYCN, cell cycle, and apoptosis.
Main Results:
- Recurrent DNA copy number aberrations are key drivers in neuroblastoma.
- Several affected genes are implicated in MYCN regulation, cell cycle control, and apoptosis.
- These genes represent potential tumor dependencies and therapeutic vulnerabilities.
Conclusions:
- Understanding copy number aberrations is crucial for neuroblastoma treatment.
- Genes within altered genomic regions offer promising targets for novel therapies.
- Further research into copy-number driven dependencies can improve outcomes for high-risk neuroblastoma.
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