Functional chromatin features are associated with structural mutations in cancer

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Structural mutations (SMs) are key drivers of cancer development.
• Breakpoint locations in DNA double-strand breaks (DSBs) show varied patterns in transcribed regions across different cancer types.
• The mechanisms behind these breakpoint patterns, potentially involving protein binding and chromatin state, are not well understood.

Purpose of the Study:

• To investigate the generalizability of the correlation between protein-DNA binding (and open chromatin) and structural mutation breakpoint locations across diverse cancer types.
• To explore potential mechanisms influencing the distribution of structural mutations in cancer genomes.

Main Methods:

• Comprehensive analysis of 457 ENCODE protein binding ChIP-seq experiments, 125 DnaseI, and 24 FAIRE experiments.
• Integration with 14,600 structural mutations from 8 diverse cancer datasets (147 samples).
• Statistical analysis of enrichment patterns of protein binding and open chromatin near mutation breakpoints.

Main Results:

• Enrichment of protein binding and open chromatin near structural mutation breakpoints (up to 200 kb) was observed in most cancers.
• Breakpoint enrichment was consistently higher in regions distant from genes compared to regions proximal to genes across all cancer types.
• A stronger enrichment effect was noted at sites with multiple protein bindings.

Conclusions:

• Protein binding and open chromatin states are consistently associated with nearby structural mutation breakpoints in various cancer datasets.
• These findings suggest a unified mechanism influencing structural mutation locations across different cancers, independent of transcriptional activity bias.
• The study highlights the role of epigenetic factors in shaping cancer-associated genomic alterations.