Somatic Mutations Enriched in Cis-Regulatory Elements Affect Genes Involved in Embryonic Development and Immune...

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Noncoding cis-regulatory variants are increasingly recognized as cancer drivers.
• Prioritizing these variants is challenging due to technical limitations.
• Active cis-regulatory elements (aCREs) offer a focused approach to identify driver mutations.

Purpose of the Study:

• To identify somatic mutations within aCREs associated with neuroblastoma tumorigenesis.
• To assess the prognostic significance of noncoding mutations in aCREs.
• To investigate the functional impact of these mutations on gene expression and patient outcomes.

Main Methods:

• Deep sequencing of 56 neuroblastoma tumor/normal DNA pairs targeting aCREs.
• Definition of aCREs using H3K27ac ChIP-seq data from neuroblastoma cell lines.
• Statistical analysis accounting for chromatin accessibility and replication timing; validation with whole-genome sequencing and Hi-C data; CRISPR-Cas9 editing for functional assessment.

Main Results:

• Identified an excess of somatic mutations in aCREs of genes including IPO7, HAND2, and ARID3A.
• Noncoding mutations in aCREs were associated with inferior overall and event-free survival.
• Mutated aCRE target genes correlated with negative prognostic markers and impaired immune response pathways.

Conclusions:

• Somatic mutations within aCREs are significant drivers of neuroblastoma.
• These noncoding mutations serve as independent predictors of poor patient prognosis.
• The study highlights a strategy for identifying regulatory element mutations in cancer development.