# Elucidating the role of the noncoding genome in neuroblastoma

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $445,909

## Abstract

Project Summary
Neuroblastoma (NB) remains one of the deadliest childhood cancers. NB exhibits a paucity of recurrent protein
coding mutations and few targetable mutations (2-5), providing the rationale for this proposal. Noncoding variants
can disrupt regulatory and/or structural DNA leading to dysregulated transcriptional programs that promote
tumorigenesis. Our objective here is to identify noncoding variants and mechanisms that drive NB. Our central
hypothesis is that germline variants and somatic mutations within noncoding regulatory regions of DNA potently
influence NB initiation, progression and/or disease relapse. We will test our hypothesis in three specific aims: 1)
Define and evaluate differences in the epigenomic landscape of NB and NB precursor cells. First, a panel
of genetically diverse human-derived NB cell lines and neural crest cells (NCC; NB precursor cells) will be
characterized. 3D chromatin architecture at all promoters will be ascertained using an ultra-high-resolution
promoter-focused Capture C approach. Cells will be further profiled by whole genome sequencing (WGS), RNA-
seq, ATAC-Seq, and ChIP-seq for histone marks and key structural proteins. Evolution of the epigenomic
landscape from NB precursor to NB cells will be assessed. Data will be integrated with transcription factor binding
site functional predictions to provide a comprehensive resource for the interpretation of noncoding variants. 2)
Identify germline noncoding variants influencing NB tumorigenesis. We will perform variant-to-gene
mapping at NB susceptibility loci identified by GWAS and identify putative causal variants mapping to open
chromatin and involved in chromatin interactions in NB precursor or NB cells. Next, rare germline noncoding
mutations from WGS will be assessed in a similar manner to identify variants interacting with known cancer
predisposition genes. Further in silico prioritization will be accomplished via clinical correlative and integrative
host-tumor analyses. The mechanism by which top prioritized noncoding variants promote NB will be determined
using genetic manipulation in cell models in combination with Capture C, ChIP-seq, RNA-seq and/or functional
studies. 3) Discover and assess biological relevance of somatic noncoding drivers of NB. We will integrate
WGS of diagnostic and relapsed NB tumors to identify noncoding mutations affecting regulatory DNA and
chromatin interactions in NB genomes. Recurrent variants will be further characterized through integration with
matched RNA-seq (n=443), DNA methylation (n=223) and clinical correlative studies. We will elucidate biological
relevance of prioritized mutations via massively parallel reporter assay (MPRA) coupled with CRISPR-based
genetic manipulation in cell models in combination with Capture C, ChIP-seq, RNA-seq and/or functional assays.
This work will have a sustained and positive impact on the field by providing substantial insights into the role of
the noncoding genome in this imp...

## Key facts

- **NIH application ID:** 10864978
- **Project number:** 5R01CA237562-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Sharon Diskin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,909
- **Award type:** 5
- **Project period:** 2021-03-12 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864978

## Citation

> US National Institutes of Health, RePORTER application 10864978, Elucidating the role of the noncoding genome in neuroblastoma (5R01CA237562-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10864978. Licensed CC0.

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