Hereditary Breast and Ovarian Cancer Driven by BRCA1/BRCA2 Variants: Chromosomal Instability Pathways, Integrative Omics-Based Stratification, Synthetic Lethality Approaches, and Evolving Therapeutic Paradigms

Background: Hereditary breast and ovarian cancer (HBOC) syndrome is predominantly driven by germline and somatic alterations in the BRCA1 and BRCA2 genes, which play central roles in homologous recombination–mediated DNA repair and maintenance of genomic stability. Loss of BRCA function leads to chromosomal instability, replication stress, and tumor evolution, creating unique biological vulnerabilities that can be therapeutically exploited. Objective: This review aims to comprehensively synthesize current knowledge on the molecular mechanisms underlying BRCA-driven carcinogenesis, with a particular focus on chromosomal instability pathways, integrative multi-omics–based tumor stratification, synthetic lethality–based therapeutic strategies, and emerging clinical paradigms in precision oncology. Methods: A narrative and integrative literature analysis was conducted using peer-reviewed studies from genomics, functional biology, translational oncology, and clinical trials related to BRCA1/BRCA2 mutations. Emphasis was placed on mechanistic insights, omics-based biomarkers, therapeutic resistance, and evolving treatment strategies, including targeted and immunotherapeutic combinations. Results: BRCA-deficient tumors exhibit profound homologous recombination deficiency, leading to characteristic genomic scars, chromosomal aberrations, and heightened replication stress. Integrative genomics, transcriptomics, proteomics, and metabolomics approaches have enabled refined stratification of BRCA-driven cancers and improved prediction of therapeutic response. Synthetic lethality, exemplified by PARP inhibition, has transformed clinical management, while emerging targets such as ATR, CHK1, WEE1, and POLθ offer new avenues to overcome resistance. Furthermore, BRCA-associated genomic instability shapes a distinct immunological landscape characterized by increased neoantigen burden and activation of innate immune pathways, providing a strong rationale for combination strategies with immune checkpoint inhibitors. Conclusion: Advances in the understanding of BRCA-mediated DNA damage response and chromosomal instability have fundamentally reshaped therapeutic approaches for hereditary breast and ovarian cancers. The integration of multi-omics data, functional genomics, and artificial intelligence–driven analytics is poised to further refine patient stratification and enable truly personalized treatment strategies. Continued efforts to address clinical, ethical, and accessibility challenges will be essential for the equitable implementation of precision oncology in BRCA-driven malignancies.