Abstract P3-04-06: Genomic and transcriptomic profiling of BRCA mutation carrier tissues reveals the landscape of early pathogenesis of BRCA1/2-associated breast cancer

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Abstract Women who harbor germline heterozygous mutations of BRCA1 or BRCA2 have a high risk of breast cancer. Our previous study showed that patient-derived, ostensibly normal BRCA2mut/+ luminal progenitor (LP) cells are more prone to exhibit sub-chromosomal copy number variations and associated DNA damage relative to non-carriers, potentially reflecting early breast tumorigenesis. Clinically assessable biomarkers for early pathological changes of BRCA1/2 mutation in LP cells remain unknown. Single-cell RNA sequencing (scRNAseq) of LP cells of BRCA1/2mut/+ carriers revealed enrichment of KIT expression (KIT+) and subsequent transcriptional factor activations were observed in LP cells of BRCA1/2mut/+ carriers relative to non-carriers. Moreover, pathway analysis uncovered that KIT+ BRCA-mutated LP cells were enriched in pathways involving DNA binding transcription activator activity and oxidative phosphorylation. These gene signature profiles were recapitulated in bulk RNA-seq of BRCA2 mut/+ carrier LP cells. Collectively, our preliminary data suggest such analyses may identify potential biomarkers for near-term risk prediction that reflect early pathogenesis of BRCA1/2-associated carcinogenesis. Following further validation via tissue microassay analysis and clinical studies, our findings may eventually assist patients and clinicians in decision making regarding the timing and necessity of preventive surgeries for BRCA1/2 mutation carriers. Citation Format: Zuen Ren, Siang Boon Koh, Kai Stewart, Nick Haradhvala, Aylin S. Dedeoglu, Isabella Vianna, Ilze Smidt, Akiko Suzuki, Taisha Joseph, Veerle Bossuyt, Esther Rheinbay, Michael Lawrence, Gad Getz, Leif W. Ellisen. Genomic and transcriptomic profiling of BRCA mutation carrier tissues reveals the landscape of early pathogenesis of BRCA1/2-associated breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-04-06.

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