A fusion-deletion genomic-event underlies poor prognosis in young patients with luminal breast cancer

Breast cancer in young patients, particularly those with the luminal subtype, exhibits more aggressive behavior and poorer clinical outcomes compared with older patients. However, the genomic mechanisms underlying this age-associated aggressiveness remains poorly understood. In this study, we integrated multi-omics data, including gene fusions, mutations, and copy number variations, to investigate age-related molecular heterogeneity in breast cancer. We identified the co-occurrence of the EEF1AKNMT::DNM3 (ED) fusion and KDM6B deletion as a novel prognostic biomarker associated with aggressive tumor biology and reduced survival in luminal breast cancer. Moreover, we discovered a widespread pattern of genomic remodeling in early-onset disease, characterized by an increased fusion burden, distinct mutational profiles, and dysregulated transcriptional programs that collectively contribute to high-risk clinical phenotypes. These findings provide mechanistic insights into the enhanced aggressiveness of breast cancer in young patients and identify potential biomarkers for improved risk stratification.