Whole-Genome Landscape of Breast Cancers from India shows Distinct Clinically Actionable Subtypes

Abstract Breast cancer remains the leading cause of cancer-related mortality among women globally, yet South Asian populations are critically underrepresented in genomic studies. Here, we present whole-genome and transcriptome analyses of over 500 treatment-naïve, clinically annotated breast tumors from India, representing the first large-scale integrative omics characterization of this population. In addition to established drivers, we identify novel significantly mutated genes, including ISM2 , TERF2 , and DHRSX , under positive selection, along with previously unreported potentially pathogenic somatic variants. Notably, the distribution of key hotspot mutations appears shaped by immune escape pressures. We uncover recurrent copy number alterations driving lipid metabolic reprogramming (e.g., NCEH1 and PLD1 amplifications) and complex structural events, including IKZF3 promoter hijacking leading to ERBB2 overexpression and TTC28 -associated genomic instability—findings not previously described in breast cancer. Mutational processes are dominated by DNA repair deficiency, APOBEC activity, and genome instability. We identify three genomic features significantly associated with poor post-surgical recurrence-free survival. Transcriptomic profiling reveals distinct intrinsic subtypes with divergent immune landscapes, including a high-risk HER2-androgenic cluster with the worst outcomes. Additionally, we find a novel transcriptomic signature that robustly captures a HER2-like transcriptional state within triple-negative breast cancer patients – with major implications for TNBC treatment. Finally, clinically actionable germline and somatic alterations are revealed with high significance, highlighting opportunities for therapeutic repurposing. Together, the study establishes a comprehensive molecular atlas of breast cancer in an underrepresented population, providing critical insights into tumour biology and advancing precision oncology.