The genetics of hereditary nonmedullary thyroid carcinoma.

Abstract

Nonmedullary thyroid carcinoma (NMTC) includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), the Hurthle cell variant of FTC, insular thyroid carcinoma, and anaplastic thyroid carcinoma. PTC is the most common and occurs with an incidence of about 1 per 20,000 per year (1). Although most NMTCs are sporadic, a familial predisposition for PTC represents an important variant. In 1997, Fagin (2) reviewed the evidence for a familial predisposition to PTC in JCEM. He appropriately concluded that there was strong evidence for a familial predisposition to NMTC as a component of known familial tumor syndromes, but that familial NMTC (fNMTC) as a distinct inherited tumor syndrome had not been unequivocally established. It is still fair to conclude that fNMTC has not been unequivocally established, because this will require the identification of a susceptibility gene for this disorder. Individuals with germline mutations of a NMTC susceptibility gene are at risk for developing NMTC. Recent observations provide further evidence for a familial predisposition to PTC and suggest that there may be three or more PTC susceptibility genes. The identification of these genes will unequivocally establish familial PTC (fPTC) as a distinct entity, provide an important diagnostic tool for the practicing physician, and clarify the molecular mechanisms of thyroid tumorigenesis. A familial predisposition to medullary thyroid carcinoma (MTC) is well recognized, and the genetic abnormalities of multiple endocrine neoplasia (MEN) types 2A and 2B have been characterized. Genetic testing has transformed the clinical approach to these patients. In contrast, a familial predisposition to nonmedullary thyroid neoplasia confronts the traditional teaching that NMTC is sporadic and not familial. However, epidemiological studies suggest that about 5% of all PTC may have a familial component (3). The results of the human genome project and powerful genetic techniques can be applied to fPTC to identify the susceptibility genes. Mutations of these genes are the earliest gene changes that predispose to development of this neoplasm. fNMTC can be divided clinically into two groups (Table 1). In the first group, PTC is the predominant clinical feature of a familial tumor syndrome. In the second group of disorders, NMTC is a relatively infrequent component of a familial tumor syndrome. There are no known familial syndromes characterized by a predominance of follicular, insular, or anaplastic thyroid carcinoma. A related group of interest is comprised of the familial syndromes that predispose to nodular goiter. This review will discuss the evidence that supports a distinct familial tumor syndrome(s) characterized clinically by a predominance of PTC and distill the clinically relevant information from these studies. It will briefly review the second group of inherited tumor syndromes characterized by NMTC as a relatively infrequent component. Clinical care suggestions are derived from this new information (Table 2).