Survival rates of women diagnosed with ovarian cancer are dismal due to our inability to identify ovarian cancer at early stages. Predictive markers for cancer predisposition would be important to identify individuals at risk. Germline mutations in BRCA1 and BRCA2 are well established risk factors for breast and ovarian cancer, yet these only occur in a small percentage of ovarian cancer cases. It has been proposed that the remaining ovarian cancer cases are caused by a combination of low penetrance cancer susceptibility alleles. Genome wide association studies (GWAS) are best used to find these moderate to low penetrance cancer susceptibility alleles that make up the polygeneic components of the disease. GWAS test the frequency of single nucleotide polymorphisms (SNPs) in cases versus controls to find the genetic differences that associate with the disease. Several candidate loci have been found for ovarian cancer. However it is unclear how they contribute to disease risk. The best way to solve this problem is to analyze the function of the candidate SNPs. A large ovarian cancer GWAS found a SNP associated with decreased risk of ovarian cancer nearest to the gene BNC2. BNC2 has also been shown to have low expression levels in ovarian cancer cells compared to normal ovarian epithelial cells. The low expression levels of BNC2 in cancer cells suggest that the protein acts as a tumor suppressor and the SNP may enhance function or expression of the gene. BNC2 has three separated pairs of C2H2 zinc finger domains suggesting that BNC2 binds to DNA and may function as a transcription regulator. We will test the hypothesis that BNC2 influences cancer progression by functioning as a transcriptional regulator acting on genes involved in cancer initiation by achieving the followin aims:
Aim 1 : To identify the DNA sequences recognized by the BNC2 ZFs.
Aim 2 : To investigate the function of BNC2 as a transcriptional regulator of cancer associated genes.
Aim 3 : To investigate how SNPs in the 9p22 locus identified in the GWAS impact the function of BNC2. We will then have a greater understanding of the function of BNC2 and how it influences ovarian cancer risk. This will ultimately lead us one step closer to predicting, preventing and treating the disease.
In most cases, by the time physicians detect ovarian cancer, it has already reached late stage disease and the chances of survival are slim. Therefore markers to identify women at risk of ovarian cancer would be beneficial. Genome-wide Association Studies have identified several loci that have a significant effect on ovarian cancer predisposition. Yet, the function of these Single Nucleotide Polymorphisms (SNPs) in these loci is unclear. The proposed project investigates the functional implications of a locus involved in predisposition to ovarian cancer. Understanding the mechanism of risk enhancement conferred by SNPs in this locus will aid in cancer prevention and treatment for patients with cancer predisposition.
|Buckley, Melissa; Gjyshi, Anxhela; Mendoza-FandiÃ±o, Gustavo et al. (2016) Enhancer scanning to locate regulatory regions in genomic loci. Nat Protoc 11:46-60|