Familial medullary carcinoma of the thyroid (MCT) is a malignant neoplasm of the calcitoninproducing C cells of the thyroid gland, inherited in an autosomal dominant pattern with a high degree of penetrance. The tumor and its premalignant precursor, C-cell hyperplasia, can be detected in affected individuals by the presence of elevated serum calcitonin levels, usually following provocative challenge with an agent that stimulates calcitonin secretion. Cytogenetic abnormalities, frequently in the form of chromosome instability, characterize certain other syndromes that are associated with a high incidence of cancer, e.g., preleukemia, Bloom's syndrome, Fanconi's anemia. Similarly, some families with a high incidence of cancer throughout the family (cancer families) sometimes display chromosome instability in clinically normal members as well as in affected individuals. These associations suggest that chromosome instability may be a visible manifestation of genetic susceptibility to neoplastic development. We are using a variety of cytogenetic techniques to study the cytogenetics of MCT in the members of a large kindred with this disease. We have made preparations from lymphocyte cultures of individuals in four categories: (1)\known affected, (2)\known to be at high risk, (3)\known to be at low or no risk and (4)\spouse controls. Positive cytogenetic findings will be correlated with the presence of disease, as defined by histological examination or positive tests of calcitonin stimulation. The overall goal is the development of a simple, definitive cytogenetic test which will identify individuals with the MCT gene in childhood. Affected individuals could then be followed closely and treated promptly (total thyroidectomy at an early stage is curative). Nonaffected individuals would be spared years of anxiety plus the cost and discomfort of yearly calcitonin stimulation tests. These cytogenetic findings should be applicable to other kindreds with this disease as well.