Temporal ordering of genomic events reveals distinct evolutionary trajectories in early-onset breast cancer

Introduction: Early-onset breast cancer (EOBC), diagnosed in women under 40, exhibits more aggressive behavior than later onset breast cancer (LOBC), with a higher recurrence rate and poorer prognosis. Despite these clinical differences, the genomic basis of EOBC remains poorly understood, making it crucial to explore these distinctions in order to elucidate age-associated genetic and tumor evolutionary features of EOBC. Methods: We performed whole-genome sequencing on 169 Korean breast cancer patients (97 EOBC, 72 LOBC) to comprehensively characterize their genomic landscapes, including single-nucleotide variants (SNVs), copy-number variants (CNVs), and structural variants (SVs). We analyzed germline & somatic driver mutations and mutational signatures to compare the etiological mechanisms between EOBC and LOBC, and reconstructed clonal architectures to determine the molecular timing and temporal ordering of key driver events in both age groups. Results: In EOBC, we observed a higher frequency of GATA3, PPM1D, and MYC alterations. The structural rearrangement landscape was characterized by enrichment of intra-chromosomal rearrangements on chromosomes 1q and 8, as well as inter-chromosomal rearrangements involving chromosomes 17 and 8. Copy-number and mutational signature analyses further showed increased prevalence of chromosomal LOH (CN13), chromothripsis-associated amplifications (CN8), and DNA damage-repair-related signatures, including D8 (replication stress) and M2 (base excision repair errors), indicating that EOBC is driven by oncogene activation and replication stress-associated genomic instability. In terms of tumor evolution, EOBC follows a rapid, oncogene-driven trajectory initiated by early TP53-inactivating mutations and PIK3CA-activating mutations, which promote tumor cell survival and proliferation. Whole-genome duplication (WGD) arises subsequently and occurs relatively early in the evolutionary course of EOBC compared with LOBC, further buffering and amplifying pre-existing genomic instability and accelerating tumor progression. In contrast, LOBC exhibited a higher frequency of PTEN mutations and WGD, which underpinned large-scale genomic alterations, including extensive tumor suppressor losses and copy-number signatures related to chromothripsis and WGD (CN25, CN6, CN7), collectively contributing to sustained genomic instability. Evolutionarily, LOBC appears to progress more gradually, beginning with 1q gains (MDM4, MCL1) and early loss of tumor suppressors that support tumor survival and invasion, with WGD typically occurring at a later stage and adding further genomic instability after prolonged tumor development. Conclusion: EOBC follows a rapid, oncogene-driven evolutionary trajectory with early genomic instability and WGD, whereas LOBC progresses more gradually with later tumor suppressor loss and WGD.