2003 Liz Tilberis Early Career Award Recipient — Douglas A. Levine, MD
Project Summary
Ovarian Cancer is the leading cause of death from gynecologic malignancies. Over the past decade we have learned much about the causes of hereditary ovarian cancer, but little is known regarding the genetic risk factors for sporadic ovarian cancer. Inherited mutations in two specific genes, BRCA1 and BRCA2, are responsible for approximately 10% of all ovarian cancer. While this is a small fraction of all ovarian cancer cases, women found to have a mutation in one of these two genes have approximately a 40% lifetime risk of developing ovarian cancer. Unfortunately, we are currently unable to predict which women will develop ovarian cancer and who will remain unaffected. One of the goals of this proposal is to help predict which women, of those with inherited mutations, are most likely to develop ovarian cancer. For the remainder of women who develop sporadic ovarian cancer, predisposing genetic factors have not been identified. There is impressive evidence to suggest a relationship between androgens and the development of ovarian cancer in women. This proposal will exploit the aromatase enzyme, a key regulator of androgen levels, to determine if it serves as a risk modifier for ovarian cancer in general and among women with hereditary disease. The scientific approach will capitalize on haplotype blocks, which are recently identified regions of low variation throughout the human genome. Prior to this discovery, studies of genetic variation relied on markers that individually had a relatively low likelihood of significant disease associations. Haplotype-based association studies are a powerful comprehensive approach to identify genetic variation underlying complex diseases like ovarian cancer. This research plan will be one of the first to use this methodology to study genetic predisposition to ovarian cancer. Our findings are expected to aid in the risk stratification and targeting individuals for therapeutic interventions in an effort to reduce the overall burden of ovarian cancer.