Abstract 2410: Copy number-based instability in breast cancer

Abstract Copy number alterations (CNAs), involving the acquisition and loss of DNA segments, are common genetic changes associated with cancer initiation and genomic instability (GI). Similar to single base substitutions, CNAs in cancer genomes often accumulate non-randomly, linked to aberrant DNA damage and repair mechanisms. Investigating higher-order CNA patterns, especially in CNA-prone malignancies like breast cancer, offers insights into GI's nature, causes, and clinical implications. While GI is historically described using predefined scores or de novo CNA signature extraction, these approaches haven't been comprehensively combined and profiled in genomically diverse diseases such as breast cancer. Fourteen pre-existing CNA scores depicting diverse GI phenomena were reintegrated within a unified computational framework. Applied to a large cohort of breast cancer patients (n = 2, 763) from TCGA and METABRIC, this framework, along with de novo CNA signature extraction, identified eight robust signatures. CNA scores and signature activities were associated with genomic features and clinical information, including subtype and patient outcomes. Breast cancer oncogenes such as ESR1, CCND1, and IKBKE were preferentially amplified by tandem duplication in a subtype-dependent manner. Additionally, two CNA signatures were characterized as harboring relatively few CNAs ("CNA quiet") within diploid and tetraploid genomes, respectively, with the latter representing an unreported subset of whole genome doubled tumors. Samples with a combination of CNA quiet genomes and low macrophage infiltration exhibited significantly better survival outcomes, independent of standard clinical risk factors. Intriguingly, several signatures coincided with the inactivation of BRCA1/2, genes critical for proficient homologous recombination (HR). These signatures showed differential activity in samples lacking BRCA1 and BRCA2, indicating a potential gene-specific CN pattern of HR deficiency. Segments assigned to another signature exhibited substantial overlap with chromothripsis-like patterns and extrachromosomal DNA (ecDNA), suggesting a common process underlying the generation of these complex GI phenomena. These findings emphasize how exploring scores and signatures can elucidate diverse mechanisms underlying CNA-driven GI in breast cancer. The relative activities of these signatures may hold notable prognostic potential, especially when integrated with other clinically relevant data modalities such as immune cell infiltration. Overall, comprehensive profiling of higher-order CNA patterns in breast cancer can not only uncover the diversity and sources of GI but also provides translational impact. Citation Format: Hannan Wong, Anna Korsakova, Andy Wu, Akila Perera, C. Pawan K. Patro, Shangying Chen, Shwetha Sundararaman, Vinay Warrier, Daniel G. Tenen, Jason J. Pitt. Copy number-based instability in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2410.