) Epidemiologic studies consistently have demonstrated a striking relationship between reproductive factors and epithelial ovarian cancer. Although increasing frequency or duration of pregnancies, breast feeding and oral contraceptive use have been shown to be protective, the molecular mechanisms underlying these relationships remain unknown. Our group and others have identified alterations in several oncogenes and tumor suppressor genes in ovarian cancers: mutations in the p53 tumor suppressor gene occur in 15 percent of advanced ovarian cancer, which leads to relative overexpression of p53 protein; and the HER-2/neu oncogene is overexpressed in 20-30% of ovarian cancers. In this study, we will test the hypothesis that epidemiologic risk factors are associated with lesions in specific genes that serve as molecular signatures of distinct etiologic pathways. The source population for these analyses is 296 epithelial ovarian cancer cases from three of eight participating Surveillance, Epidemiology and End Results (SEER) tumor registries of the Cancer and Steroid Hormone (CASH) study, a population-based case-control study conducted in the early 1980s. The three participating SEER centers include Connecticut, Detroit, and Iowa. Personal interview data from the CASH study data base and paraffin tissue blocks of the primary epithelial ovarian cancers will be accessed. Paraffin blocks of the ovarian cancers will be sent to Duke University for the analysis of alterations in p53 and HER-2/neu. Hypothesis to be tested will focus on reproductive history and hormone use and will include: 1) that p53 overexpression in ovarian cancer is associated with uninterrupted ovulation; 2) that reproductive/hormonal risk factors are associated with the development of ovarian cancers with HER-2/neu overexpression;3) that there are correlations between genetic alterations, reproductive/hormonal risk factors and clinicopathologic characters of ovarian cancer. Clarifications of the relationship between epidemiologic risk factors and molecular genetic features of ovarian cancers promises to facilitate definition of subsets of this heterogenous disease, which has important implications for the development of effective prevention and screening strategies.
| Schildkraut, J M; Halabi, S; Bastos, E et al. (2000) Prognostic factors in early-onset epithelial ovarian cancer: a population-based study. Obstet Gynecol 95:119-27 |
| Schildkraut, J M; Bastos, E; Berchuck, A (1997) Relationship between lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer. J Natl Cancer Inst 89:932-8 |
