It is now possible for women to learn if they carry cancer-predisposing mutations in BRCA1 and BRCA2 and, if so, to take steps to prevent ovarian cancer including (1) periodic screening with CA125 and transvaginal ultrasonography, beginning between the ages of 30 and 35 years or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family, and (2) consider risk-reducing salpingo-oophorectomy by age 40 or when childbearing is complete.

We have a great deal of work still to do to provide women with noninvasive options for prevention, but, meanwhile, knowledge of genetics continues to save lives. For the many women whose mothers or sisters carried such mutations and died of ovarian and/or breast cancer, but do not carry the mutation themselves, genetic knowledge brings tremendous relief.

Many families severely affected with ovarian cancer do not carry mutations in BRCA1, BRCA2, or any of the known ovarian or breast cancer susceptibility genes. We propose to identify new genes for inherited predisposition to ovarian cancer by fully sequencing the entire genomes of familial ovarian cancer patients with no mutations in any known ovarian or breast cancer genes. We have selected five high-risk ovarian cancer families that have histological profiles that are unlikely to result from mutation in any of the known ovarian cancer genes.

We will use "next generation sequence" technology and a bioinformatics pipeline to identify all potentially deleterious mutations in these families. We have successfully piloted this approach on a genome of a normal healthy control and validated and characterized many novel mutations.

This project will be the first application of complete human genome sequencing to the identification of genes for inherited ovarian cancer. The identification of new ovarian cancer genes will allow prevention strategies to be extended to hundreds of families for which causal ovarian cancer genes are currently unknown. The discovery of new ovarian cancer genes will also serve to better identify women at risk, to allow closer surveillance of women at highest risk, to stimulate design of new prevention strategies based on genetic evidence, and to offer a better understanding of the biological pathways involved in ovarian cancer development.