Breast cancer remains a major global health challenge1. Here, to comprehensively characterize its genomic landscape and the clinical significance of genomic characteristics, we analysed whole-genome sequences from 1,364 clinically annotated breast cancers, with transcriptome data available for most cases. Our study expands the repertoire of oncogenic alterations and identifies novel driver genes, recurrent gene fusions, structural variants and copy number alterations. Timing analyses on copy number alterations suggest that genomic instability emerges decades before tumour diagnosis, and offer insights into early initiation of tumorigenesis. Pattern-driven genomic features, including mutational signatures2, homologous recombination deficiency3, tumour mutational burden and tumour heterogeneity scores4, were associated with clinical outcomes, highlighting their potential utility as predictive biomarkers for clinical evaluation of treatments such as CDK4/6 and HER2 inhibitors, as well as adjuvant and neoadjuvant chemotherapy. These findings highlight the power of large-scale, clinically annotated whole-genome sequencing in advancing our understanding of how genomic alterations shape patient outcomes.
