On the Prevalence of Familial Nonmedullary Thyroid Cancer in Multiply Affected Kindreds

Abstract

Clinical and genetic studies of familial nonmedullary thyroid cancer (FNMTC) have yielded conflicting results concerning the aggressiveness of the tumors, and uncertainty of their genetic makeup. In most reports of multiply affected families, the composition of the kindreds has favored families of 2 affected members. Using data for differentiated thyroid cancer (DTC) provided by the Surveillance Epidemiology and End Results (SEER) branch of the National Cancer Institute, and fine-needle aspiration data from Mayo Clinic, I found that the likelihood of 2 cases of sporadic DTC (RR) in a 9-member first-degree family was 1.25% of all DTC families, amounting to 39.4% of 306 multi-hit families reported in the literature. To study the remaining affected families I used the Bernouilli trials model of exact probability. The 60.6% of non-RR, multiply affected families are mostly concentrated in kindreds of 2 to 5 affected members. In 2-hit families, 62%-69% of affected members are sporadic (RR) cases. In families having 3 or more affected members, fewer than 6% have 1 or more sporadic (R) cases, and fewer than 0.15% have 2 or more. In families of 3 to 5 affected members, more than 96% of affected members have the familial (F) trait. Approximately 1 of 338 DTC cases carries the F-trait. Since approximately 40% of multiply affected member first-degree kindreds of DTC, and a significant majority of 2-hit families, are composed of clinically evident, sporadic cases only clinical and genetic investigations of FNMTC should center on families of 3 or more affected members.

ENDOCRINE TUMOURS: Familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis

“…The identification of FNMTC still relies on clinical data. Therefore, further study investigating the clinical and genetic research should choose the patients with three or more affected members to represent the familial form of the disease in order to reduce the potential selection bias as some authors have recommended (7).…”

Familial vs sporadic papillary thyroid carcinoma: a matched-case comparative study showing similar clinical/prognostic behaviour

“…In a retrospective matched-case control study of FNMTC, the majority being PTCs, Maxwell et al (24) reported that familial cases tend to have, but not significantly, improved DFS and disease-specific survival. In a classical study (34), based on probability calculation analysis, Charkes pointed out that up to 60% of familial PTCs diagnosed in families with only two affected members might, actually, represent a fortuitous aggregation of sporadic cases, suggesting that the disease may be more accurately diagnosed in families with three or more affected members (17,21). This fact could, therefore, also contribute to misestimate the aggressiveness of familial PTC.…”

Familial thyroid cancer: a review

“…Statistical estimates suggest that a grouping of two family members with NMTC could represent the concurrence of sporadic tumors, but thyroid tumors in three or more members in kindred, or the diagnosis of PTC in men and children, is more suggestive of a familial predisposition. [24][25][26][27][28][29][30][31][32][33][34][35][36][37]61 Although non-medullary thyroid cancer is mostly sporadic, evidence for a familial form, not associated with other Mendelian cancer syndromes described above (eg FAP and CS), is well documented and thought to cause more aggressive disease. The search for a genetic susceptibility locus for FNMTC started about a decade ago.…”