Familial Nonmedullary Thyroid Carcinoma—The Case for Genetic Susceptibility

James A. Fagin, M.D.

University of Cincinnati School of Medicine Cincinnati, Ohio 45267

Address correspondence and reprint requests to: James A. Fagin M.D., Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, 231 Bethesda Ave., Rm. 5564, Cincinnati, Ohio 45267-0547. Email: FaginJA@UC.edu.


    Introduction
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 Introduction
 References
 
Cancers of follicular thyroid cells are relatively rare, with age-adjusted incidence rates ranging from about 0.9–5.2/100,000 cases per year (1). At least 80% of these are papillary thyroid carcinomas, which are more common in women. The major known risk factor for papillary thyroid carcinoma is prior exposure to radiation. The effects of radiation on cancer risk are dose-dependent. Relative risk (RR) of thyroid cancer was 4.0 among children exposed to a mean dose to the thyroid of 9 rads (2). In a separate study, the RR was 12.9 for children exposed to 1–49 rads, and 196 for greater than 600 rads (3). A lower age at the time of exposure has been consistently associated with a higher RR for thyroid cancer, a phenomenon that was strikingly apparent in the pediatric thyroid carcinomas arising after the Chernobyl nuclear disaster (4).

Over the years, there have been multiple reports of clustering of cases of papillary carcinomas in families (5, 6, 7, 8, 9). Most of the literature consists of descriptions of individual family pedigrees. This has resulted in uncertainty as to whether the familial association represents evidence of genetic predisposition to the disease, exposure to a common environmental triggering event, increased susceptibility to environmental effects, or a chance occurrence. A comprehensive analysis of families of all cases of papillary carcinoma diagnosed in Iceland between 1955 and 1984 revealed that 3.8% of the propositi had a first degree relative with thyroid carcinoma, a higher than expected frequency that was not, however, statistically significant (although there was a significantly increased risk in male relatives) (10). Stoffer et al. (11) studied families from 226 consecutive papillary thyroid carcinoma patients from a private practice, and concluded that between 3.5 and 6.2% had at least one affected relative. Four individuals with familial papillary carcinoma had a history of radiation in childhood that may have contributed to the expression of the phenotype. Some of the pedigrees reported by Stoffer et al. had multiple affected individuals (11). Ron et al. reported a population-based case-control study of the Connecticut Tumor Registry, in which a 5-fold excess risk of nonmedullary thyroid cancer was found in close relatives (12, 13). These three studies are the most informative concerning the existence of familial predisposition to nonmedullary thyroid carcinoma and yielded results consistent with this notion. Environmental factors may have played a role in at least some of these cases, as some of the affected individuals had a history of radiation exposure.

In this issue of the Journal of Clinical Endocrinology and Metabolism, Burgess et al. (14) (see page 345) describe two Tasmanian families with seven and four affected members, respectively. Individuals from the largest kindred had co-existent multiple nodular goiter and a pattern consistent with an autosomal dominant mode of inheritance. Although the underlying pathogenesis of thyroid tumorigenesis in this family is unknown, it is possible that the proliferative drive introduced by the presence of multinodular goiter may have allowed a putative genetic predisposition to papillary carcinoma to manifest with greater penetrance. The second family consisted of affected monozygotic twins and two of their offspring. None of the individuals from either family had features compatible with familial adenomatosis polyposis (FAP), or Gardner’s syndrome. Although the evidence is not yet conclusive, these kindreds further support the existence of a distinct syndrome of familial papillary thyroid carcinoma.

An increased predisposition to papillary carcinoma is well established in certain families with adenomatous polyposis, an autosomal condition characterized by the presence of multiple adenomatous polyps of the intestine (1, 15, 16). The association with thyroid cancer extends to Gardner’s syndrome, a variant of FAP characterized by numerous intestinal adenomas, osteomas, soft tissue lesions, and other extracolonic neoplasms (17, 18). Thyroid cancers in FAP exhibit a marked female preponderance (female: male ratio 8:1), and are more common under the age of 30. Women below 35 yr of age with FAP have been estimated to have a 160-fold higher risk of thyroid carcinoma than normal individuals (1). Papillary carcinomas from patients with FAP are commonly multifocal, well-encapsulated, and often display unusual histopathological features, such as areas of cribriform, solid and spindle cells within the tumors (19). Predisposition to FAP is conferred by germline inactivating mutations of the APC gene, which maps to chromosome 5q21 (20, 21). Colorectal neoplasms from patients with FAP frequently exhibit loss-of-heterozygosity at this locus, consistent with a role for APC as a tumor suppressor gene, requiring loss of function of both alleles in order for the recessive phenotype to emerge. It is not known whether thyroid carcinomas from patients with FAP also have somatic mutations of the wild-type allele of the APC gene. The presence of extracolonic neoplasms in patients with FAP is also genetically determined and is not caused by the nature of the structural defect of the APC gene itself. This predicts that one or more "modifier" genes may act in concert with APC to alter the predisposition to tumor formation at extracolonic sites, such as the thyroid gland. Indeed, there is good evidence for the existence of such "modifier" genes, capable of modulating the expression of the FAP phenotype. Examination of FAP kindreds demonstrates that family members inheriting the same APC mutation differ dramatically in tumor burden (i.e. number of polyps). To determine the possible genetic basis for this variability, MacPhee et al. (22) have used a mouse strain with multiple intestinal neoplasia (Min), harboring a nonsense mutation in exon 15 of APC, a defect also found frequently in human FAP kindreds. When Min mice were crossed with different mouse strains, there was a dramatic difference in the number of intestinal polyps in the F1 progeny of animals harboring the Min mutation according to the genetic background. The genetic locus conferring the difference in tumor burden was then mapped by interspecific backcross analysis to mouse chromosome 4, and a candidate "modifier" gene identified (secretory phospholipase A2) (22). Localization of gene modifiers in humans or in mice with adenomatous polyposis may prove to be an expedient way to identify candidate genes conferring predisposition to familial thyroid cancer. It is noteworthy that mutations of APC are not prevalent in sporadic thyroid neoplasms, indicating that inactivation of this gene is not likely by itself to predispose to sporadic thyroid tumor formation (23).

Thyroid tumors have also been reported in other familial syndromes. They are the most frequent extracutaneous manifestation of Cowden’s disease (multiple hamartoma syndrome), being observed in two thirds of patients; they include benign thyroid lesions (adenomas, goiter, thyroglossal duct cyst) and follicular thyroid carcinoma (24). There are case reports describing the association of thyroid carcinoma in patients with Peutz-Jeghers syndrome (25) and ataxia-telangiectasia (26). In patients with multiple endocrine neoplasia type1 (MEN1), thyroid disease is observed mostly as benign lesions (nodular hyperplasia, goiter, adenoma) and far more rarely as a malignancy (27). The gene conferring predisposition to MEN1 is located on chromosome 11q13 and is believed to function as a tumor suppressor (28). Pancreatic, pituitary, and parathyroid tumors from patients with MEN1 frequently exhibit loss of heterozygosity at this locus, presumably resulting in loss-of-function of the normal allele. Loss of heterozygosity at chromosome 11q13 is also found in sporadic follicular thyroid neoplasms, suggesting that the putative tumor suppressor gene at this locus plays a significant role in thyroid tumorigenesis (29, 30).

Exposure to a common environmental insult, such as external radiation, may represent an alternative mechanism for the familial clustering of patients with papillary thyroid carcinoma. The most significant sources of exposure have been after therapeutic irradiation and through environmental disasters (31). As a result of the accident at the Chernobyl nuclear power plant in 1986, millions of Curies of short-lived radioiodine isotopes were released in the fallout. The absorption of radioiodines from ingestion of contaminated food and water and through inhalation led to internal exposure to the thyroid gland that was 3–10 times higher in children than in adults. An increased incidence of thyroid cancer in children from the most contaminated areas of Belarus (i.e. Gomel region) was noted as early as 3 yr after the accident (32). Between 1991 and 1992, the incidence of childhood thyroid cancer in Belarus was 60-fold greater than before the disaster (33), and this increase now extends to contaminated regions of Ukraine and Southwest Russia. In Belarus, the risk of thyroid carcinoma was inversely correlated with the distance of residence location from the source of radioactive contamination and with age at the time of exposure: the greatest number of children subsequently developing thyroid cancer were less than 4 yr of age at the time of the accident (4). Radiation is known to induce DNA strand breaks, but the precise genetic targets are likely to vary according to the cell type. Recent studies suggest that activating mutations of the ret proto-oncogene resulting in the aberrant expression of the tyrosine kinase domain of the ret receptor (i.e. ret/PTC rearrangements) are common in post-Chernobyl papillary thyroid carcinomas (31, 34, 35). However, ret/PTC is also found with high prevalence in children without a history of radiation exposure, although the precise types of ret rearrangement differ. It is possible that rearrangements of ret may be a direct result of radiation on thyroid cells, either through exposure of individuals to high doses (e.g. as in the case of Chernobyl patients) or increased susceptibility to radiation effects (e.g. in pediatric thyroid carcinomas found in the general population). If this is the case, it is conceivable that at least some families with papillary thyroid carcinoma may inherit a partial impairment in mechanisms controlling repair of double strand DNA breaks, a common target of radiation damage. Thus, an interplay between genetic susceptibility and environmental carcinogens may be significant in some kindreds with papillary carcinoma. A high prevalence of ret/PTC rearrangements in tumors from affected individuals from large kindreds would be consistent with this view, as frequency of this genetic event is low in sporadic tumors from adult patients.

In conclusion, familial papillary thyroid carcinoma may be a true clinical entity, although its pathogenesis remains complex. Until the epidemiological data is more definitive, attempts to establish the putative genetic basis for this condition may be best focused on candidate genes or on potential gene "modifiers" of the phenotype of other inherited cancer syndromes, such as familial adenomatous polyposis.

Received October 17, 1996.

Accepted October 23, 1996.


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