GENETIC ANALYSIS USING THE GILDA RADNER REGISTRY

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Mutations of the BRCA1 gene are thought to be involved in at least 70% of families with excess incidence of cancers of the ovary and breast. Little is known about predisposing genes in the remaining breast/ovarian cancer families, or in families with excess ovarian cancer but little or no breast cancer. It is now feasible to identify other predisposing genes for ovarian cancer. Critical to this effort is DNA from many large ovarian cancer families. Because such families are rare, the Gilda Radner familial Ovarian Cancer Registry is an important resource for such study. The Registry, established at the Roswell Park Cancer Center in 1981, currently comprises some 1000 U.S. families containing at least two ovarian cancer diagnoses among first- or second-degree relatives. We propose to identify 100 of the most informative families to obtain blood and/or archival tissue specimens for genetic linkage analysis. We will address the following questions: i) What proportion of ovarian cancer families are due to the BRCA1 gene? ii) What epidemiologic features (e.g. mean age at onset, ethnicity, histologic subtype or malignant potential of tumor, other site-specific cancer occurrence) distinguish linked from unlinked families? iii) Do unlinked families show linkage to other loci? If, as seems almost certain, the BRCA1 gene is cloned within the project period, we also will examine the spectrum of other diseases associated with specific BRCA1 mutations, and assess which epidemiologic characteristics distinguish mutation carriers who develop cancer from those who do not. To accomplish these aims, we will select some 260 families containing three or more reported ovarian cancers and contact family members to complete the pedigrees and verify reported cancers against medical records. We then will select 100 of the most informative of these families and obtain blood and/or archival tissue specimens from affected members and first-degree relatives of affected members. Finally, we will isolate viable lymphocytes and DNA from blood samples and analyze the specimens for linkage and mutations in candidate genes. Use of this large registry to map predisposing genes for ovarian cancer and characterize families linked at different loci offers these benefits: it will identify women at genetically high risk who can be targeted for screening and intervention, and it will allow classification of ovarian cancers into genetic subtypes, thereby facilitating the study of etiologic factors and the planning of strategies for screening and prevention.