High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities.

Ductal carcinoma in situ is a non-obligate precursor lesion of breast cancer. Often detected by mammography, most cases are managed through surgical and/or radiotherapy approaches. Today, it is not possible to predict which patients will progress to invasive disease. Here, we evaluate high-depth whole-genome sequenced ductal carcinoma in situ, enriched for high-grade clinical lesions, to understand whether deep WGS could reveal biological insights and/or personalized therapeutic vulnerabilities that may be targetable. We find genomic locations that are likely susceptible to producing the initiating lesion for structural variations prone to subsequent evolution, termed SHOREs. We additionally highlight individualized therapeutic potential that would otherwise not be appreciable without whole genome sequencing. We posit that holistic whole genome sequencing profiling could offer a more precise stratification approach, discerning higher-risk cases for prospective clinical studies on personalized therapies, from truly low-risk cases suitable for active monitoring.