BARD1 and breast cancer genetic predisposition: case-control study and HRD signature analysis.

BARD1 germline pathogenic variants (gPV) have been primarily associated with moderate breast cancer risk but their rarity limits accurate risk assessment and tailored follow-up guidelines. Our study evaluates the association between BARD1 gPV and breast cancer while exploring the role of BARD1 in mammary oncogenesis. In this case-control study, 7,309 women with breast cancer and no gPV identified in the French hereditary breast and ovarian cancer (HBOC) gene panel at the Institut Curie were compared to 57,681 female controls from the gnomAD European non-cancer database. Tumors were analyzed for biallelic BARD1 inactivation and homologous recombination deficiency (HRD). A significant association was observed between BARD1 gPV and breast cancer (OR = 5.2, 95% CI [3-8.9], p = 5.9 × 10- 9). Molecular data were obtained and interpretable for seven tumors. Among these, two triple-negative (TN) primary tumors exhibited both biallelic BARD1 inactivation via loss of heterozygosity (LOH) and an HRD phenotype; one metastasis displayed LOH without HRD. All non-TN primary tumors lacked both biallelic inactivation and HRD. We found a strong enrichment of BARD1 gPV among women selected for personal and family history of breast cancer, reinforcing their relevance for genetic testing for suspected hereditary predisposition. Tumor analysis suggests a potential association between biallelic inactivation of BARD1 and the HRD phenotype in TN primary breast tumors, providing new treatment perspectives.