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Review Article Multiple Endocrine Neoplasia Type 2 And J Med Genet 2000;37:817–827 817 J Med Genet: first published as 10.1136/jmg.37.11.817 on 1 November 2000. Downloaded from Review article Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis Jordan R Hansford, Lois M Mulligan Abstract diseases for families. Elucidation of genetic Multiple endocrine neoplasia type 2 (MEN mechanisms and their functional consequences 2) is an inherited cancer syndrome char- has also given us clues as to the broader acterised by medullary thyroid carcinoma systems disrupted in these syndromes which, in (MTC), with or without phaeochromocy- turn, have further implications for normal toma and hyperparathyroidism. MEN 2 is developmental or survival processes. The unusual among cancer syndromes as it is inherited cancer syndrome multiple endocrine caused by activation of a cellular onco- neoplasia type 2 (MEN 2) and its causative gene, RET. Germline mutations in the gene, RET, are a useful paradigm for both the gene encoding the RET receptor tyrosine impact of genetic characterisation on disease kinase are found in the vast majority of management and also for the much broader MEN 2 patients and somatic RET muta- developmental implications of these genetic tions are found in a subset of sporadic events. MTC. Further, there are strong associa- tions of RET mutation genotype and disease phenotype in MEN 2 which have The RET receptor tyrosine kinase led to predictions of tissue specific re- MEN 2 arises as a result of activating mutations of the RET (REarranged during quirements and sensitivities to RET activ- 1–5 ity. Our ability to identify genetically, with Transfection) proto-oncogene. RET encodes a receptor tyrosine kinase expressed primarily high accuracy, subjects with MEN 2 has 6–8 revolutionised our ability to diagnose, in neural crest and urogenital precursor cells. It is a developmentally important gene, re- predict, and manage this disease. In the http://jmg.bmj.com/ past few years, studies of RET and its nor- quired for kidney morphogenesis, maturation of peripheral nervous system lineages, and for mal ligand and downstream interactions 6910 and the signalling pathways it activates diVerentiation of spermatogonia. Like have clarified our understanding of the other receptor tyrosine kinases, the RET roles played by RET in normal cell protein comprises extracellular, transmem- survival, proliferation, and diVerentia- brane, and cytoplasmic domains (fig 1). The extracellular sequences include regions with tion, as well as in disease. Here, we review homology to the cadherin family of cell on September 24, 2021 by guest. Protected copyright. the current knowledge of the normal func- adhesion molecules and a large cysteine rich tions of RET and the eVects of mutations region.11–14 Twenty seven of 28 cysteine resi- of this gene in tumorigenesis and in dues within the cysteine rich domain are normal development. (J Med Genet 2000;37:817–827) conserved between species, suggesting a criti- cal role for these residues in formation of Keywords: multiple endocrine neoplasia type 2; RET; intramolecular disulphide bonds, and thus in Department of receptor tyrosine kinase determining the tertiary structure of RET pro- Pathology, Queen’s teins.11 13 The intracellular tyrosine kinase University, Kingston, domain is similar to that of other receptor tyro- Ontario K7L 3N6, Recognition of cancer as a genetic disease has sine kinases and functions in phosphorylation Canada J R Hansford contributed to the rapid advances of recent of key tyrosine residues involved in interaction L M Mulligan years in our ability to identify, diagnose, and with downstream targets and activation of sig- treat human neoplasia. Nowhere have the nalling pathways. Department of inroads made in these areas been clearer, or Under normal conditions, the RET receptor Paediatrics, Queen’s had more impact, than in the inherited cancer is activated through a multicomponent com- University, 20 Barrie syndromes, where the presence of multiple, plex involving members of two distinct groups Street, Kingston, Ontario K7L 3N6, often diverse, disease symptoms and tumour of proteins: a soluble ligand of the glial cell line Canada types have made diagnosis and screening highly derived neurotrophic factor (GDNF) family, J R Hansford problematical. The genetic characterisation of and a cell surface bound coreceptor of the L M Mulligan many of these diseases in the past few years has GDNF family receptors á (GFRá) protein provided us with the tools for recognition, family (fig 2). The GDNF proteins are Correspondence to: 15 Dr Mulligan, screening, and management and has had a members of the TGF-â subfamily and have [email protected] huge impact on the perceived burden of these all been shown to act as potent neuronal www.jmedgenet.com 818 Hansford, Mulligan J Med Genet: first published as 10.1136/jmg.37.11.817 on 1 November 2000. Downloaded from 123 456789101112131415161718192021 5' 3' RET9 RET43 RET51 Cadherin-like domain Tyrosine kinase domain Cysteine rich domain domain Extracellular domain Transmembrane Intracellular domain Duplication MEN 2A FMTC MEN 2B Figure 1 Schematic diagram of the structures of the RET gene and protein. Protein domains are indicated. Positions of MEN 2 mutations are shown relative to the 21 RET coding exons and to their corresponding position in the RET protein. Only mutations found in multiple independent families and/or for which functional significance has been confirmed are shown. survival factors.16 Four members of this family nent. MEN 2 may be classified into three sub- have been identified to date, including GDNF, types based on their occurrence. MTC, phaeo- neurturin (NTN), persephin (PSP), and ar- chromocytoma (PC), and hyperparathyroidism temin (ART).16 (HPT) characterise MEN 2A, the most Although all four GDNF family members common of these subtypes. PC, a tumour of act as the ligands for RET, they do not bind the adrenal chromaYn cells, occurs in approxi- RET directly but first interact with a cell mately 50% of MEN 2A patients, while only surface bound coreceptor of the GFRá family 15-30% of cases develop HPT or parathyroid (fig 2). These coreceptors do not have adenomas.20–22 PC is also present in approxi- http://jmg.bmj.com/ intracellular domains but are anchored to the mately 50% of those with the MEN 2B cell membrane via a glycosyl- subtype. Parathyroid involvement is rare in phosphatidylinositol (GPI) linkage.17 18 There these cases, and characteristic developmental are four GFRá family members identified to abnormalities including marfanoid habitus, date (GFRá-1-4).16 GDNF family members thickened corneal nerves, and ganglioneuro- form high aYnity interactions with a specific matosis of the buccal membranes and the 19 23 24 member of the GFRá family. GFRá-1 prima- gastrointestinal tract are prevalent. MEN on September 24, 2021 by guest. Protected copyright. rily binds GDNF, GFRá-2 binds NTN, 2B is considered to be the most aggressive of GFRá-3 binds ART, and GFRá-4 binds PSP the MEN 2 subtypes, with a median age of (fig 2).16 All of the diVerent GDNF/GFRá onset 10 years earlier than seen in MEN 2A.19 24 complexes bind to, and activate, RET. The The third subtype of MEN 2, familial MTC GDNF and GFRá family members have (FMTC), is characterised by the presence of distinct and overlapping expression patterns,16 MTC in multiple family members (four or suggesting that activation of RET by formation more) as its only disease phenotype.25 Families of ligand receptor complexes is a tightly with a smaller number of MTC cases but with- regulated process. It is thus not surprising that out other phenotypes are more diYcult to clas- we see significant disease phenotypes associ- sify as they may represent small FMTC ated with aberrant RET activation. families or MEN 2A families in which PC or HPT have not yet manifested. FMTC is gener- Multiple endocrine neoplasia type 2 ally considered the least aggressive of the three (MEN 2) MEN 2 subtypes with a later onset than MEN MEN 2 is an inherited cancer syndrome char- 2A or 2B.25 acterised by medullary thyroid carcinoma (MTC), a tumour of the neural crest derived Genetics of MEN 2 parafollicular C cells responsible for the MEN 2 is inherited in an autosomal dominant production of calcitonin.19 While MTC, or its fashion with variable, age dependent pen- precursor lesion C cell hyperplasia, are the etrance.26 Unlike other cancer syndromes, most common disease phenotypes in MEN 2 which are associated with inactivation of patients (clinically significant disease occurring tumour suppressor genes, each of the MEN 2 in 70% of cases), other lesions are also promi- subtypes arises as a result of activating www.jmedgenet.com MEN 2 and RET 819 J Med Genet: first published as 10.1136/jmg.37.11.817 on 1 November 2000. Downloaded from NTN A GDNF PSP ART RET α GFR -2 GFRα-1 GFRα-4 GFRα-3 B http://jmg.bmj.com/ P P P P Figure 2 (A) Schematic diagram showing the members of the RET multimeric signalling complexes and the primary interactions of the diVerent GDNF family ligands and GFRá family members. (B) Predicted model of RET activation by on September 24, 2021 by guest. Protected copyright. its ligand and coreceptor molecules.18 Soluble ligands bind cell surface bound GFRá family members which, in turn, present the ligands to RET,mediating its dimerisation and autophosphorylation. mutations of the RET proto-oncogene. Mis- each of the above mutations, a cysteine residue sense mutations aVecting cysteine residues in normally involved in the intramolecular disul- the RET extracellular domain are found in phide bonds that determine the tertiary struc- patients with MEN 2A (fig 1, table 1). Single ture of RET is unpaired and can form base pair substitutions in one of five codons, intermolecular bonds with other RET 609, 611, 618, 620 (exon 10) or 634 (exon 11), molecules.31–33 The outcome is dimerisation are found in >98% of MEN 2A families.32728 and constitutive activation of the RET tyrosine (fig 1, tables 1 and 2).
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