Priyanka Verma, Ph.D. (Year 1)

ABSTRACT

BRCA1 plays an essential role in the error-free repair of DNA double-strand breaks. Loss-of-function mutation in BRCA1 increases the lifetime risk for breast and ovarian cancers by ~77% and ~44%, respectively. BRCA1 mutation typically results in triple-negative breast cancers and high-grade serous ovarian carcinoma, two highly aggressive malignancies with limited therapeutic options. These cancers therefore significantly reduce lifespan and quality of life. Notably, efforts in the past decade have uncovered multiple ways by which the risk for these cancers can be effectively mitigated. Prophylactic surgery, which includes bilateral mastectomy and salpingo-oophorectomy, has been shown to significantly reduce the risk of cancer development in carriers with pathogenic BRCA1 mutation. In addition, chemopreventive and hormonal therapy options have also been shown to be effective. However, there is a knowledge gap on which BRCA1 mutation(s) will invariably result in cancer development. This knowledge is critical to assess which individuals would truly benefit from surgical or other preventative measures. As per CinVar, there are a total of 14,662 germline mutations reported in the BRCA1 gene. Amongst these ~36% of mutations belong to the group of conflicting classification, uncertain significance, and likely pathogenic categories. Hence, we urgently need a viable approach to accurately predict the significance of the germline BRCA1 mutations. To address this knowledge gap, we propose to develop a high-content screening assay to predict the pathological relevance of germline BRCA1 mutations. The screening approach has been designed to predict the pathogenicity in an unbiased manner and it overcomes the limitations of CRISPR-based strategies that have been previously used. The pathogenic mutation identified in the screen will be functionally characterized to assess how the variant impacts the double-strand break and replication fork repair functions of BRCA1. Findings from this work will lay a strong foundation for a biomarker platform that can robustly predict which BRCA1 mutation carriers should take the available cancer risk-reducing measures, thereby delaying or even preventing the onset of aggressive cancers. This assessment will potentially result in a longer lifespan for BRCA1 mutation carriers. Furthermore, the feasibility and simplicity of our proposed approach would be amenable to screening cancer-predisposing mutations in multiple other genes involved in error-free repair of DNA double-strand breaks.

Summary and description in lay language
Mutations in the BRCA1 gene contribute to approximately 70% of triple-negative breast cancers and 50% of high-grade serous ovarian carcinoma. These two cancer types are highly aggressive and significantly reduce life span. In addition, the current therapeutic measures are associated with severe side effects that hamper quality of life. Fortunately, there are multiple approaches that can significantly reduce the risk of BRCA1 mutation cancer development. This entails surgical removal of breast and fallopian tissue, hormonal therapy, and other drug regimens. However, there are a total of 14,662 reported mutations in the BRCA1 gene. Some of these mutations likely predispose to cancer, but it is unclear which ones do. Therefore, it is difficult to predict which individuals would benefit from the preventative measures. In this proposal, we aim to develop a robust assay that can accurately predict which BRCA1 mutations are cancer-predisposing. This knowledge will be imperative to inform the carriers of BRCA1 mutations to take appropriate prevention measures in a timely manner. This information will help delay or even prevent cancer onsets in individuals with BRCA1 mutations, enabling them to live a longer and healthier life.