Familial medullary carcinoma of the thyroid (MCT) is a malignant neoplasm of the calcitonin-producing C-cells of the thyroid gland, inherited in an autosomal dominant pattern with a high degree of penetrance. The tumor and its pre-malignant 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 studies of this disease in several laboratories have produced conflicting results indicating possible genetic heterogeneity among families in which the gene for MCT is present. In 3 MCT families that we have been studying chromosome instability and consistent karyotypic abnormalities did not appear to be present. MCT tumors, however, were karyotypically abnormal. Chromosomal fragile sites, which may be heritable or spontaneous, can be experimentally induced in susceptible individuals. Some fragile sites are now known to correspond to breakpoints associated with certain cancers and/or oncogene locations. We propose to continue the cytogenetic study of familial MCT with the specific aim of answering the following questions: 1. Is there increased chromosomal fragility in familial MCT? 2. Is any specific fragile site associated with MCT? 3. What is the chromosome complement of medullary carcinoma of the thyroid, i.e. of the tumor tissue per se? 4. Can high-resolution banding of the tumor cell chromosomes be accomplished? Our ultimate goal is to find a cytogenetic test for the presence of the MCT gene and/or cytogenetic guide to the appropriate probes to study this disease at the molecular level. Methods will involve modifications of known, routine cytogenetic procedures.