Familial Ovarian Cancer Candidate Resequencing

Beyond BRCA1/BRCA2, relatively little is known about genetic susceptibility to ovarian cancer. Although carriers of both BRCA1 and BRCA2 mutations have much higher risks of ovarian cancer than non-carriers, those with a BRCA1 mutation have the highest risk. It is doubtful there are sufficient BRCA1/BRCA2-mutation negative families with multiple cases of ovarian cancer for adequate statistical power, particularly those with enough informative individuals with DNA samples, owing to the high mortality associated with the disease. We are therefore pursuing an analysis of site-specific ovarian cancer probands using a subset of the available subjects from the Ovarian Cancer Association Consortium (OCAC) investigators.

From the Gilda Radner Familial Ovarian Cancer Registry and NCI we have available nearly 100 probands with ovarian cancer from families with at least one other case of ovarian cancer and no cases of early-onset breast cancer – site-specific ovarian cancer families. All subjects have been screened negative for BRCA1/BRCA2 mutations. Using one of three strategies for selecting candidate genes (genes in which common variants are associated with ovarian cancer risk, genes whose mRNA expression differentiates lymphoblastoid cell lines from BRCA1 carriers and non-carriers, and genes associated with a murine model of cancer metastasis), we will resequence them to identify mutations that may segregate within the families. In addition, within the OCAC, in which ~20,000 case-control subjects with DNA have been assembled for genetic studies, we have the opportunity evaluate rare variants (minor allele frequencies, maf, 0.5% - 5%) as susceptibility alleles in addition to common variants. This project will complement the majority of other efforts concentrating on common variation as characterized in the HapMap project.