Noncoding regulatory mutations contribute to the aberrant gene expression profile of neuroblastomas.
- 1University of Alabama at Birmingham
Abstract
Comprehensive analyses of whole-genome and exome sequencing data from high-risk neuroblastoma tumors have identified relatively few recurrent and clinically actionable protein-coding driver mutations at initial diagnosis. This suggests that noncoding genetic variations that alter regulatory sequences and impact gene expression are important drivers of neuroblastoma tumorigenesis. Allele-specific expression (ASE), which quantifies differences in expression between the two alleles of a gene, is a powerful approach for identifying genes with altered dosage resulting from cis-regulatory variation. In this study, we compared ASE profiles of 156 neuroblastoma patients with 220 adrenal gland tissues from the Genotype-Tissue Expression (GTEx) Project to identify 1,363 neuroblastoma-specific ASE genes. We demonstrated that these genes were enriched for biological processes relevant to neuroblastoma pathogenesis including chromatin remodeling, protein ubiquitination, and sympathetic nervous system development, and were preferentially associated with the adrenergic transcriptional program. To elucidate the genetic mechanism underlying aberrant expression of neuroblastoma-specific ASE genes we integrated our ASE data with somatic copy number alterations (SCNA) and somatic mutation profiles. We observed that although many neuroblastoma specific ASE genes were associated with chromosomal gains and losses, a substantial subset was located within copy-number-neutral genomic regions. These genes showed significant enrichment for noncoding somatic single-nucleotide variants (SNVs) within intronic and distal intergenic neuroblastoma-specific open chromatin regions. Furthermore, functional analyses revealed that many of these SNVs disrupt transcription factor binding sites for GATA3, a core component of the regulatory circuitry that maintains the adrenergic identity of neuroblastoma cells, and neuroblastoma-specific ASE genes harboring such mutations were significantly more likely to belong to the GATA3 regulon than expected by chance. Together, our findings identify novel molecular targets of noncoding regulatory mutations in neuroblastoma and highlight the important yet underappreciated contribution of noncoding genetic variation to neuroblastoma tumorigenesis.
Related
- Non-Coding Structural Variants in Regulatory Regions and High Polygenic Burden May Jointly Contribute to Early-Onset Familial Hashimoto’s Thyroiditis
- Expression of the long noncoding RNA Neat1 in saliva, blood, and ventromedial hypothalamus of pigs exposed to psychosocial stressors.
- Point mutations and complex variants impact gene expression and addiction-related behaviors in Heterogeneous Stock rats
- Enhancer Activity-informed Gap GEne Regulatory Network (EAGER) to model Drosophila gap gene expression on the entire anterior-posterior (A-P) axis
- Comprehensive characterization of transposable element expression reveals regulatory circuitry and clinical implications in cancers
BibTeX
@misc{jones2026noncoding,
title = {{Noncoding regulatory mutations contribute to the aberrant gene expression profile of neuroblastomas.}},
author = {B. Jones and G. Seth and A. N. Robertson and A. Sen},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.10.743941},
url = {https://www.biorxiv.org/content/10.64898/2026.08.10.743941v2},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Noncoding regulatory mutations contribute to the aberrant gene expression profile of neuroblastomas.
AU - B. Jones
AU - G. Seth
AU - A. N. Robertson
AU - A. Sen
PY - 2026
DA - 2026/08/10
PB - bioRxiv
DO - 10.64898/2026.08.10.743941
UR - https://www.biorxiv.org/content/10.64898/2026.08.10.743941v2
AB - Comprehensive analyses of whole-genome and exome sequencing data from high-risk neuroblastoma tumors have identified relatively few recurrent and clinically actionable protein-coding driver mutations at initial diagnosis. This suggests that noncoding genetic variations that alter regulatory sequences and impact gene expression are important drivers of neuroblastoma tumorigenesis. Allele-specific expression (ASE), which quantifies differences in expression between the two alleles of a gene, is a powerful approach for identifying genes with altered dosage resulting from cis-regulatory variation. In this study, we compared ASE profiles of 156 neuroblastoma patients with 220 adrenal gland tissues from the Genotype-Tissue Expression (GTEx) Project to identify 1,363 neuroblastoma-specific ASE genes. We demonstrated that these genes were enriched for biological processes relevant to neuroblastoma pathogenesis including chromatin remodeling, protein ubiquitination, and sympathetic nervous system development, and were preferentially associated with the adrenergic transcriptional program. To elucidate the genetic mechanism underlying aberrant expression of neuroblastoma-specific ASE genes we integrated our ASE data with somatic copy number alterations (SCNA) and somatic mutation profiles. We observed that although many neuroblastoma specific ASE genes were associated with chromosomal gains and losses, a substantial subset was located within copy-number-neutral genomic regions. These genes showed significant enrichment for noncoding somatic single-nucleotide variants (SNVs) within intronic and distal intergenic neuroblastoma-specific open chromatin regions. Furthermore, functional analyses revealed that many of these SNVs disrupt transcription factor binding sites for GATA3, a core component of the regulatory circuitry that maintains the adrenergic identity of neuroblastoma cells, and neuroblastoma-specific ASE genes harboring such mutations were significantly more likely to belong to the GATA3 regulon than expected by chance. Together, our findings identify novel molecular targets of noncoding regulatory mutations in neuroblastoma and highlight the important yet underappreciated contribution of noncoding genetic variation to neuroblastoma tumorigenesis.
ER -