Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update

Abstract

Context: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients.

Evidence acquisition: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin.

Evidence synthesis: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC.

Conclusions: The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC.

Figure 1.

The RET protein. Abbreviations: ART, artemin; CLD, cadherin-like domains; CRD, cysteine-rich domain; GDNF, glial-derived neurotrophic factor; GFL, glial-derived neurotrophic factor family ligands; GFRα (1–4), GDNF family α receptors; Ki, kinase insert region; NTN, neuturin; PSP, persephin; SP, signal peptide; TK, tyrosine kinase domain; TM, transmembrane domain. The position of major RET phosphorylation sites (Y905, Y1015, and Y1062) are marked, as are other phosphorylation sites and signaling pathways.

Figure 2.

The RET gene, the RET protein, and RET point mutations associated with MEN2A, MEN2B, and FMTC. RET gene structure with coding exons numbered 1 to 20 is shown as the central figure in gray. Alternative splicing in exon 19 generates 2 alternative mRNAs, coding for RET-51 (1114 residues) when exon 19 is spliced to exon 20 or RET-9 (1072 residues) when exon 19 remains unspliced. Moreover, alternative splicing to another exon (exon 21) causes the synthesis of the C-terminal part of another less abundant RET isoform, RET-43. In this figure, only RET-51 is represented, whereas RET-9, RET-43, and the alternative exon 21 are not. The RET protein is represented on the left in blue and red. Amino acid residues, numbered 1 to 1114, are shown to the left of the figure. The extracellular RET domain (with the signal peptide [SP], 4 cadherin-like domains [CLD1–4], and a cysteine-rich domain [CRD]), the transmembrane domain (TM), and the intracellular tyrosine kinase domain (TK) are represented. The RET TK is split into 2 subdomains (TK1 and TK2) by an insert region (Ki). The positions of reported RET point mutations associated with MEN2A, MEN2B, and FMTC are shown to the right of the RET gene. The mutations causing MEN2A and MEN2B are shown in black, whereas the mutations for FMTC are shown in red. An asterisk denotes homozygous mutations. Some of the reported RET mutations have no function studies demonstrating that the specific mutation is a bona fide gain-of-function mutation. Not included in Figure 2 are reports of deletions, insertions, duplications, or multiple mutations. This information, as well as references for each point mutation or genetic alteration, is included in Supplemental Table 1. [Modified from Figure 5 in J. W. de Groot et al: RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006;27:535–560 (163), with permission. © The Endocrine Society.]