The Breakome of BRCA1 and BRCA2 Pathway Mutation Carriers Reveals Early Processes in Breast Oncogenesis

Abstract

DNA double-strand breaks (DSBs) can lead to genomic instability in cancer. Cells rely on an efficient DNA damage response (DDR) to maintain their DNA integrity and prevent oncogenic transformation. However, the early events that connect recurrent DNA damage to oncogenesis are not yet fully understood. Here, using next generation sequencing we comprehensively surveyed genomes to identify DSBs in primary cells of non-malignant carriers of BRCA1 and BRCA2 mutations (BRCAmut), categorized as high-risk patients, to characterize the effects of homologous recombination (HR) loss on cancer initiation. We demonstrate that the landscape of physiological DSBs in BRCAmut mammary epithelial cells differs from that of healthy controls and resemble more the DSB pattern observed in breast cancer cells. Our results reveal that proto-oncogenes and tumor suppressors contain more breaks in BRCAmut samples, and that genes with a high number of DSBs tend to be more highly expressed. These genes containing a high number of DSBs are also often mutated in breast cancer tumors. Finally, genes with high DSBs in mammary epithelial cells from women with BRCAmut exhibit a strong correlation with homologous recombination repair. Together, our findings underscore the impact of BRCA loss on the early stages of carcinogenesis and highlight future possibilities for early cancer detection. Graphical abstractWhen BRCA is intact, genes that are highly broken are properly repaired via HR, preserving DNA integrity. When BRCA is mutant, impairing its function, highly broken transcriptional DSB genes emerge, no longer able to be efficiently repaired via HR, and are found at genes related to cancer signaling. Breakome of enriched breaks at high-risk model resembles breast cancer breakome, and breaks can be found in genes known to be frequently mutated in breast cancer.