A resource of breast cancer pedigrees has been developed through the ascertainment of nearly 100 unselected male and 250 female breast cancer patients as well as 620 patients selected for having a family history of the disease. Included in the resource are examples of defined clinico-genetic entities in each of which breast cancer is an integral component. These include the Li-Fraumeni syndrome, Muir's syndrome, Cowden's disease, breast-ovarian cancer, and site specific breast cancer. Because of their association with breast cancer, their being examples of dominantly inherited conditions, their relatively early ages at onset and involving indentifying lesions and tumors, these entities offer a unique opportunity for investigating the genetics of breast cancer within relatively homogeneous groups of pedigrees. The present intent is to utilize each of the entities in a linkage study in an attempt to localize each of the gene loci influencing breast cancer susceptibility to specific chromosome and/or to link them to genetic markers. Each entity will be evaluated for linkage between the susceptibility allele and an array of polymorphic marker loci determining cell surface antigens, plasma proteins, red cell enzymes, and immunoglobulin types. DNA markers comprised of cloned DNA sequences isolated from human tumors or tumor cell lines and viral oncogene probes will be added to the array during the coming year. Initial effort to date has been directed toward examining a previously reported linkage between a susceptibility allele for breast and ovarian cancer and the marker locus for glutamate pyruvate transaminase (GPT). This proposed linkage is being examined in 17 pedigrees. Preliminary analysis of 5 of the most complete of these pedigrees has provided evidence of small but positive lod scores with the GPT. After completion of sampling and analyses of the breast-ovarian pedigrees, effort will shift to analysis of 19 pedigrees with site-specific breast cancer. These will be followed by 10 pedigrees with the Li-Fraumeni syndrome, and last, those with Muir's syndrome and Cowden's disease, and those ascertained from among the families of unselected male and female breast cancer patients. This project should provide insight into the genetics of breast cancer and the organization of the human genome; it might also provide a means by which high risk individuals could be identified through linked markers prior to the onset of tumors.