Medullary thyroid cancer (MTC) occurs sporadically in most (75%) cases or is inherited as part of a syndrome as seen in Multiple Endocrine Neoplasia Type 2 (MEN2). Virtually all patients with MEN2, including familial MTC (FMTC), have RET germline mutations. RET mutations are detected in approximately 50% of sporadic cases. MTC is a malignant tumor of parafollicular C-cells, which are derived from the neural crest. These cells express an important receptor tyrosine kinase (RTK), which mediates cellular growth, proliferation, and survival. The gene that codes for the RTK is the RET gene, and it is the most commonly implicated gene in both sporadic and inherited MTC.1
Hereditary MTC may occur as part of MEN2 syndrome and has an incidence of approximately 1 in 30,000 individuals. MEN2 is categorized into 2 distinct types: MEN2A and MEN2B. Familial MTC is a subtype of MEN 2A.1,2
Virtually all patients with MEN2 syndrome have associated RET germline mutations inherited in an autosomal dominant pattern that mainly affect exons 10, 11, and 16.3 Mutations in exons 5, 8, 13, 14, and 15 have also been described but are less common.4 Family members with inherited MTC usually share the same mutation, however, penetrance is variable and phenotypic expression of classic MEN2 differs between patients with identical mutations.1
In families with MEN2A, the most common RET mutations (90%) are missense mutations involving codons located in the extracellular region: 609, 611, 618, and 620 (exon 10), and 634 (exon 11). In more than 60% of these cases, the involved codon is 634. One defect associated with high penetrance for MTC in MEN2A is the RET C634W mutation. Additionally, patients with the genotype C634R are associated with a higher incidence of distant metastases at diagnosis.5 While very rare, some families have no identifiable RET mutations.1
In MEN2B, 95% of patients have a specific M918T RET mutation affecting exon 16. Other less commonly documented mutations are A883F (2% to 3%) and a double-mutation V804M/Y806C at codons 804 and 806. Rare germline double-point mutations in codons 804 and 904 have also been reported. Patients with mutations in codons 883 and 918 present with MTC at a younger age and have an increased risk for distant metastasis and disease-related mortality. While MEN2B may be inherited, most cases (75%) are the result of de novo germline mutations.1 These mutations can be passed to future generations in an autosomal dominant pattern.
Familial MTC is considered a subtype of MEN2A syndrome. Both conditions are associated with RET proto-oncogenic mutations, however, for unexplained reasons, patients with FMTC do not develop hyperparathyroidism or pheochromocytomas as seen in MEN2A. Unlike MEN2A and 2B syndromes, the germline mutations associated with FMTC are dispersed throughout the RET gene.
Sporadic MTC accounts for the majority (approximately 75%) of all cases of the disease, and it typically presents between the fourth and fifth decade of life. Point mutations to RET are the most common type of defect in sporadic MTC and may also include small deletions and/or insertions. The Met918Thr mutation is the most prevalent RET somatic point mutation, followed by alterations affecting codon Cys634.5
RAS mutations, specifically to H-RAS and K-RAS, have also been described, but their occurrence is rare.1
1. Wells SA Jr, Asa SL, Dralle H, et al.; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. doi:10.1089/thy.2014.0335 2. Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med. 2011;13(9):755-764. doi:10.1097/GIM.0b013e318216cc6d 3. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-460. doi:10.1038/363458a0 4. Da Silva AMA, Maciel RMB, Da Silva MRD, Toledo SRC, De Carvalho MB, Cerutti JM. A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003;88(11):5438-5443. doi:10.1210/jc.2003-030997 5. Ferreira CV, Siqueira DR, Ceolin L, Maia AL. Advanced medullary thyroid cancer: pathophysiology and management. Cancer Manag Res. 2013;5:57-66. doi:10.2147/CMAR.S33105
Article reviewed by Harshi Dhingra, MD on July 1, 2021.