Ovarian cancer risk stratification using circulating miRNAs to assess BRCAness

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Abstract Current strategies to prevent ovarian cancer deaths remain limited. Unlike breast and colon cancer, clinical trials for early detection of ovarian cancer have not been effective at reducing ovarian cancer deaths. In contrast, risk- reducing salpingo-oophorectomy for women with germline mutations in BRCA1/2 reduces the risk of ovarian cancer death by more than 95%. However, since current guidelines limit genetic testing to individuals with a personal or close family history of breast or ovarian cancer, only 10% of the estimated 1 million Americans with BRCA1/2 mutations are aware of their mutation status. We have shown that BRCA1/2 mutation carriers have a distinct serum microRNA (miRNA) profile which can be used to rapidly identify likely mutation carriers. In this proposal, we will use previously collected sample and datasets to discover the generalizability of this miRNA profile to other potentially high-risk groups. We will examine the serum miRNA profiles of both BRCA1/2 mutation carriers as well as carriers of mutations in other DNA repair genes and women with no discernible germline mutation but a strong family history of breast or ovarian cancer. Samples will be classified in terms of BRCAness, i.e., how closely they resemble BRCA1/2 mutation carriers versus healthy controls with average cancer risk. We will determine whether the BRCA1/2 miRNA profile is restricted to alterations in these specific genes or reflects a more general deficiency in DNA repair which could increase the risk of ovarian cancer. Independently, we will test whether the BRCAness miRNA profile is sufficient as an ovarian cancer risk triage tool, even in the absence of known genetic information. Using a case-control format, we will compare baseline miRNA profiles among a study population of average risk women who were enrolled in an ovarian cancer screening trial. We will calculate whether cases were more likely to have a BRCAness miRNA profile at study entry compared to controls. The final result of these studies will be to test whether serum miRNAs can serve as a biomarker to identify more women at risk for ovarian cancer who could benefit from risk-reduction strategies. This group can then be prioritized for future biologic studies and clinical trials.