Abstract 767: Genomics and transcriptomics profiling of BRCA mutation carriers revealed 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. The 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 BRCA1/2 mutation carriers revealed enrichment of KIT expression (KIT+) and subsequent transcriptional factor activations were observed in LP cells of BRCA1/2 mutation carriers relative to non-carriers. Moreover, overrepresented 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 mutation carrier LP cells. Collectively, our preliminary data suggest such analyses may identify potential biomarkers of the risk prediction for early pathogenesis of BRCA1/2 mutation carriers. Following validation of our findings via tissue microassay analysis and clinical trials, we hope to eventually assist clinicians in their decision making of prophylactic surgeries for BRCA1/2 mutation carriers. Citation Format: Zuen Ren, Po-Han Lin, Siang Boon Koh, Kai Stewart, Nick Haradhvala, Aylin S Dedeoglu, Ilze Smidt, Akiko Suzuki, David Li, Win Thant, Sarah Mueller, Taisha Joseph, Veerle Bossuyt, Michael Lawrence, Gad Getz, Leif W. Ellisen. Genomics and transcriptomics profiling of BRCA mutation carriers revealed the landscape of early pathogenesis of BRCA1/2-associated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 767.

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