Modeling double strand break susceptibility to interrogate structural variation in cancer

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Structural variants (SVs) are crucial in cancer, yet their origins and functions remain unclear.
• SVs are often linked to DNA double-strand break (DSB) repair errors.
• Understanding DSB mechanisms is key to deciphering SVs in cancer.

Purpose of the Study:

• To develop quantitative, genome-wide models of DSB susceptibility.
• To investigate the mutational mechanisms underlying DSB formation.
• To identify regions under selection pressure for SVs in tumors.

Main Methods:

• Experimentally quantified DSB frequencies in cell lines.
• Integrated chromatin and sequence features for model development.
• Applied DSB susceptibility models to tumor data.

Main Results:

• Developed accurate genome-wide DSB susceptibility models.
• Identified SV hotspots potentially under positive selection in tumors, enriched for oncogenes.
• Discovered SV coldspots under purifying selection, enriched for regulatory elements.

Conclusions:

• DSB susceptibility models provide a robust framework for inferring selection on SVs in cancer.
• These models help distinguish neutral mutation patterns from selected events.
• The findings offer new insights into the landscape of SVs in tumor evolution.