Between 5 and 10% of all individuals will develop a thyroid nodule in their lifetime. Preoperative diagnostic techniques offer relatively low specificity and consequently, a large number of patients undergo unnecessary surgery, and yet others who harbor malignant tumors are inappropriately left untreated. These diagnostic difficulties stem from major gaps in our understanding of the biology and cellular pathophysiology of thyroid growth disorders. There is now growing evidence that tumor progression and neoplastic phenotype is determined by sequential additive genetic lesions. Activating mutations of oncogenes in addition to loss or inactivation of certain genes, which believed to be negative regulators of growth, may be associated with neoplasia. Many of these putative tumor suppressor genes are believed to act in a recessive manner, since both copies must be lost or inactivated in order for the neoplastic phenotype to be expressed. We have observed that thyroid tumors have a high prevalence of point mutations of the ras genes, and that these are found with about equal frequency in both benign and malignant neoplasms. We postulate that additional mutations must occur in the thyroid cell to bring about the malignant phenotype. There is no information on the possible role of tumor suppressor genes in the pathogenesis of human thyroid tumors. The current proposal is designed to localize regions in the genome which may contain such recessive tumor suppressor genes. We will localize and eventually characterize putative tumor suppressor genes in thyroid neoplasms by performing cytogenetic and allelotype studies of sporadic benign and malignant thyroid neoplasms, and of established thyroid carcinoma cell lines. We will also perform cytogenetic and allelotype studies in thyroid tumors from families with an inherited propensity to develop thyroid neoplasms. Ultimately, we will perform detailed mapping of chromosome/s regions found to be deleted with high frequency and in a non-random manner, with particular emphasis on the region/s which may be involved in determining the transition between benign and malignant thyroid neoplasms.
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