Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin (114130)-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2 (see 171400)/familial medullary thyroid carcinoma ... Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin (114130)-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2 (see 171400)/familial medullary thyroid carcinoma (FMTC) syndromes (summary by Abu-Amero et al., 2006). Thyroid cancer derived from follicular epithelial cells is referred to as nonmedullary thyroid cancer and comprises several subtypes; see 188550.
About 75% of medullary thyroid carcinoma is sporadic; these cases are unilateral. Bilateral multifocal medullary carcinoma is a cardinal feature of autosomal dominant multiple endocrine neoplasia type II (MEN2A; 171400). In addition, there are cases of familial medullary ... About 75% of medullary thyroid carcinoma is sporadic; these cases are unilateral. Bilateral multifocal medullary carcinoma is a cardinal feature of autosomal dominant multiple endocrine neoplasia type II (MEN2A; 171400). In addition, there are cases of familial medullary thyroid carcinoma in which there are no extrathyroid manifestations of multiple endocrine neoplasia; otherwise the behavior of the tumor is the same as that in the hereditary disease. Such families were observed by Farndon et al. (1986). Primary localized cutaneous amyloidosis (PLCA), which has been observed with MEN2A, was reported also in a family in which multiple affected members had an association only with medullary thyroid carcinoma (Ferrer et al., 1991). Rakover et al. (1994) described 2 sibs in whom isolated familial medullary carcinoma of the thyroid was diagnosed at the ages of 16 and 19 years. Hirschsprung disease was identified at the age of 1 year in both of them. Twelve other members of the family had medullary carcinoma of the thyroid. The authors stated that, although this was the first report of an association between Hirschsprung disease and isolated familial medullary carcinoma of the thyroid, the association should not be surprising because of the known association of both with mutations in the RET gene (164761).
Gimm et al. (1999) used SSCP analysis of 16 exons of NTRK1 (191315) from 31 sporadic MTCs and observed variants in 5 exons (exons 4 and 14-17). Sequence analysis demonstrated 1 sequence variant each in exons 4, 14, ... Gimm et al. (1999) used SSCP analysis of 16 exons of NTRK1 (191315) from 31 sporadic MTCs and observed variants in 5 exons (exons 4 and 14-17). Sequence analysis demonstrated 1 sequence variant each in exons 4, 14, 16, and 17, and 4 different variants in exon 15. Differential restriction enzyme digestion specific for each variant confirmed the sequencing results. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (C1810T; 191315.0008) and codon 613 (G1838T; 191315.0009) of exon 15 always occurred together, possibly representing linkage disequilibrium. The frequencies of the sequence variants in germline DNA from patients with sporadic MTC did not differ significantly from those in a race-matched control group. Marsh et al. (2003) identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4; see 601496) and their ligands glial cell line-derived neurotrophic factor (600837), neurturin (602018), persephin (602921), and artemin (603886) that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC. Abu-Amero et al. (2006) identified nonsynonymous germline mitochondrial DNA (mtDNA) mutations in both normal and tumor tissue from 20 (76.9%) of 26 cases of medullary thyroid carcinoma, including 9 (69.2%) of 13 sporadic cases and 11 (84.6%) of 13 familial cases; 10 of 13 familial cases were patients with MEN2. The familial cases tended to have transversion mtDNA mutations rather than transition mutations. All 13 familial cases also had germline RET mutations. Abu-Amero et al. (2006) suggested that mtDNA mutations may be involved in medullary thyroid carcinoma tumorigenesis and/or progression.