Targeting Germline BRCA1-Associated Breast Cancer Through Transcriptome-Guided Immunoprevention

Women with germline BRCA1 variants face a high lifetime risk of breast cancer, necessitating novel immunoprevention strategies. While the BRCA1 -mutant tumor immune microenvironment (TME) is known to be immunologically active, the specific, targetable alterations that distinguish malignant tumors from the BRCA1 -mutant normal tissue of the same carrier remain undefined. We performed integrated transcriptomic and immunologic profiling on a unique cohort of trio BRCA1 -mutant breast tumors, their matched adjacent and distant normal tissues, and separate normal breast tissues from tumor-free women harboring pathogenic germline BRCA1 variants. This within-carrier design enables precise dissection of tumor-specific transcriptional and immune microenvironmental changes while controlling for both germline BRCA1 background and host immune context. Our analysis revealed a "hot but suppressed" TME, with high CD8+ T-cell infiltration counteracted by PD-L1/CTLA4 upregulation. We uncovered that BRCA2 is upregulated in tumors, where its high expression paradoxically correlates with a "cold," T-cell-excluded immune phenotype. Concurrently, we identified an 80-gene "public" antigen signature, prioritizing five lead candidates ( LEMD1 , EPYC , H3C13 , H3C14 , and H4C15 ), that are, critically, most highly expressed in these "cold," high- BRCA2 tumors. The upregulation of Lemd1 was subsequently confirmed in the Brca1-deficient mouse model. These findings identify BRCA2 upregulation as a marker of an immune-suppressed state in BRCA1 -mutant tumors and highlight candidate targets for BRCA -mutant patient-specific preventative vaccine development.