Abstract
Breast cancer is the most prevalent cancer affecting women world-wide and poses a significant health burden to the New Zealand population with approximately 3,600 women diagnosed annually. Māori and Pacific wahine are disproportionately affected and experience the poorest health outcomes. The BRCA1 gene encodes a tumor suppressor that preserves the integrity of the genome through its role in repairing double-stranded DNA breaks via homologous recombination. Pathogenic variants in BRCA1 are associated with an approximately 72% cumulative lifetime risk of developing breast cancer by the age of 80. Individuals with pathogenic BRCA1 variants exhibit variation in age at diagnosis, cancer subtype, and family history. Risk of cancer can vary due to BRCA1 variant location and type, as well as genetic modifiers elsewhere in the genome, making it difficult to choose appropriate preventative strategies. Previous genetic association studies have shown that deletions overlapping BRCA1 are associated with greater risk of breast cancer compared to single nucleotide variants such as missense, nonsense, splice and indel variants. A possible cause for these findings is a novel genetic compensation response called transcriptional adaptation which involves the upregulation of protective genes through the degradation of mRNA containing premature termination codons (PTC). These degraded mRNA fragments may trigger upregulation of related genes leading to genetic compensation. The aim of this project was to identify genes that respond to potential BRCA1- associated transcriptional adaptation, and to verify these in an in vitro model. Bioinformatic analysis of RNA sequencing data in DESeq2 found 36 differentially expressed candidate genes. While endogenous expression in an in vitro model could not validate selected candidate genes WNK4 and RND2, they enhanced understanding of how the transcriptional adaptation response could occur in breast cancer cells. Differential gene expression comparison between wild type cell lines and cell lines containing a BRCA1 variant causing a PTC provided 69 further candidate genes worth further exploration such as SERPINA5, PLK2 and CMKT1. These will provide a greater understanding into the mechanisms underlying the risk of developing BRCA1 related breast cancer, enhancing patient care and health outcomes.