Molecular profiling of breast cancer in native American women reveals distinct genomic and transcriptomic features.

Breast cancer outcomes vary across populations, yet Native American women remain scarcely represented in tumor-genomic resources, limiting population-specific molecular insights. We generated matched somatic mutation, copy-number, and RNA-seq profiles for 17 breast tumors from Native American women and performed race-stratified comparisons with White cases from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) cohort (TCGA-BRCA). We observed population-associated differences across molecular layers, including higher mutation frequencies in ARID1B, NOTCH4, and MHC class II genes (HLA-DRB1/HLA-DRB5) in Native American tumors, and broader CNV alterations in White tumors. Integrative analyses highlighted antigen processing/presentation and cell-adhesion pathways, with class II alterations in Native American tumors and class I gains (e.g., HLA-A/HLA-B) plus CD274 amplification in White tumors, suggesting differences in immune visibility and checkpoint modulation. We also noted contrasts in nucleotide-excision-repair involvement (ERCC5/POLE mutations vs ERCC1/CUL4A CNV gains), and mutational-signature analysis indicated greater MMR- and AID/POLE-associated exposures in the White cohort. To our knowledge, this study provides an initial multi-omics characterization of breast tumors from Native American women and offers a resource and hypotheses for larger, harmonized studies to assess prognostic and therapeutic relevance.