Pituitary (2006) 9:179–192 DOI 10.1007/s11102-006-0263-4
RET and neuroendocrine tumors Yoshiki Murakumo · Mayumi Jijiwa · Naoya Asai · Masatoshi Ichihara · Masahide Takahashi
Published online: 10 October 2006 C Springer Science + Business Media, LLC 2006
Abstract The RET proto-oncogene encodes a receptor tyrosine kinase that is a main component of the signaling pathway activated by the glial cell line-derived neurotrophic factor family ligands. Gene targeting studies revealed that signaling through RET plays a crucial role in neuronal and renal organogenesis. It is well-known that germline mutations in RET lead to the human inherited diseases, multiple endocrine neoplasia type 2 (MEN 2) and Hirschsprung’s disease, and that somatic rearrangements of RET cause papillary thyroid carcinoma. Due to marked advances in understanding of the molecular mechanisms of the development of MEN 2, a consensus on MEN 2 management associated with RET status is being reached and currently put into general use as a guideline. In this review, we summarize progress in the study of RET from bench to bedside, focusing on pathophysiology of neuroendocrine tumors. Keywords RET . Tyrosine kinase . Signaling pathway . Germline mutation . Neuroendocrine tumors . MEN 2 Introduction Signals raised by wide-ranging extracellular stimuli such as growth factors and cytokines and mediated by cell surface
Y. Murakumo () · M. Jijiwa · N. Asai · M. Ichihara · M. Takahashi Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan e-mail:
[email protected] M. Takahashi Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
receptors regulate normal cell activities, including proliferation, differentiation, and motility. Aberrations in such signaling pathways cause unusual cell activities; disruption of signals results in inhibition of cell proliferation and differentiation, and constitutive activation of signals sometimes triggers neoplastic cell growth, resulting in an increased predisposition to cancer. The RET (rearranged during transfection) proto-oncogene encoding a receptor tyrosine kinase was discovered in 1985 in an NIH3T3 transfection assay as a gene rearranged in the transfection procedure [1–3]. The resulting rearranged fusion protein showed transforming activity on NIH3T3 cells, indicating an oncogenic feature of RET. Several years later, the physiological function of RET, which is essential for the development of the enteric nervous system and kidney, became clear by tissue distribution analyses and gene ablation studies [4–9]. Both features of RET are closely associated with human diseases caused by germline RET mutations. Gain-offunction mutations or gene rearrangements in RET enhance the oncogenic feature, leading to development of multiple endocrine neoplasia (MEN) type 2 or papillary thyroid carcinoma (PTC), respectively [10–14], and loss-of-function mutations in RET abolish the physiological function of RET, causing Hirschsprung’s disease [15, 16]. In this review, we summarize normal RET function and the signaling pathway through RET, and then describe the molecular mechanisms of development of human neuroendocrine tumors and their management associated with RET alterations.
RET protein structure and its physiological roles in organogenesis The RET gene is localized on chromosome 10q11.2 containing 21 exons [17, 18]. The RET protein is composed Springer
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of extracellular and intracellular parts, the former including four cadherin-like motifs and a cysteine-rich domain, the latter including a tyrosine kinase domain [19–21]. Three splicing variants of RET transcripts are generated by alternative splicing at the 3 terminal region of the RET gene, resulting in elaboration of three RET protein isoforms: short (RET9), middle (RET43), and long (RET51), of which RET9 and RET51 are the main products in cells [22, 23]. RET expression studies in rodent embryos gave important information on RET function. RET expression was detected mainly in the developing peripheral and central nervous system, including neural crest cells, cranial ganglia, dopaminergic and noradrenergic neurons, motor neurons of the spinal cord, dorsal root ganglia, and enteric neuroblasts, as well as in the excretory system such as the nephric ducts, ureteric buds, and collecting ducts [4–6, 24]. These expression studies indicate that RET has important roles in the development and differentiation of the nervous system and the kidney. Gene targeting studies of the RET proto-oncogene confirm RET function in embryogenesis. Consistent with the findings obtained in the expression studies, RET knockout mice showed renal agenesis or severe dysgenesis, and lack of enteric neurons and superior cervical ganglia [7, 8]. In addition, it was shown that in Ret-/- mice, neuronal precursors throughout the entire sympathetic nervous system fail to migrate and project axons properly [25]. These studies indicate that RET plays a critical role in neuronal and renal organogenesis. It is important to note that RET expression is also detected in human tumors of neural crest origin such as neuroblastoma, pheochromocytoma, and medullary thyroid carcinoma, suggesting the involvement of RET in human carcinogenesis [26–29]. Using gene targeting technology, de Graaff et al. established mutant mice expressing only Ret9 or Ret51 [30]. They found that monoisoformic Ret9 mice, which lack Ret51, are viable and appear normal, whereas monoisoformic Ret51 animals, which lack Ret9, have kidney hypoplasia and aganglionosis of the distal gut, indicating that Ret9 and Ret51 have different signaling properties in vivo during renal development and histogenesis of the enteric nervous system. The difference of signaling through Ret9 and Ret51 was studied further by two other groups. Tsui-Pierchala et al. showed that the phosphorylation status of Ret9 is different than that of Ret51 and that the two RET isoforms did not associate with each other in sympathetic neurons. They also found that the signaling complex associated with Ret9 was markedly different from the Ret51-associated signaling complex, suggesting functional differences between Ret9 and Ret51 in vivo [31]. Lee et al. reported that Ret51 but not Ret9 could promote the survival and tubulogenesis of mouse inner medullary collecting duct cells, suggesting that Ret51 signaling is related to differentiation events in later kidney organogenesis [32].
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Signaling pathway through RET receptor kinase In 1996, the glial cell line-derived neurotrophic factor (GDNF), which is structurally related to members of the TGFβ (transforming growth factor-beta) superfamily, was revealed to be a RET ligand protein [33–35]. Soon afterwards, the other three GDNF family ligands (GFLs), neurturin (NRTN), artemin (ARTN), and persephin (PSPN), were also identified to be RET ligands [36–38]. To activate the RET receptor kinase, GDNF requires another co-receptor component, GDNF family receptor (GFR) α1, a glycosylphosphatidylinositol (GPI)-anchored protein, to form a GDNF-GFRα1-RET heterotrimer on the cell surface membrane on GDNF stimulation, and thereby activate the RET signaling pathway [39]. So far, four GPI-anchored coreceptors (GFRα1–4) have been identified, and it has been revealed that GDNF, NRTN, ARTN, and PSPN preferentially use GFRα1, GFRα2, GFRα3, and GFRα4, respectively, as ligand-binding co-receptors for RET activation [40–45]. Gene targeting experiments showed compatible results with the findings of RET signaling in vitro. Gdnf–/– and Gfrα1–/– mice displayed similar phenotypes to Ret–/– mice, showing lack of enteric neurons and renal agenesis or severe dysgenesis [7, 46–50]. Nrtn–/– and Gfrα2–/– mice showed absence of parasympathetic cholinergic innervation in the lacrimal and submandibular salivary glands and severe reduction in the small bowel [51, 52]. Artn–/– and Gfrα3–/– mice have deficits in the sympathetic nervous system, being without the superior cervical ganglion (SCG) or with small SCGs [53, 54]. Pspn–/– and Gfrα4–/– mice showed normal development and behavior, but displayed hypersensitive cerebral ischemia or reduced thyroid calcitonin content, respectively [55, 56]. Although the relation between the phenotypes of Pspn–/– and Gfrα4–/– mice and RET function is not clear at present, these findings suggest that the preferential ligandreceptor complexes of GFLs and GFRαs have specific roles in the RET-mediated signaling pathway in vivo. GFL stimulation triggers RET dimerization and phosphorylation on specific tyrosine residues present in the intracellular domain, leading to activation of tyrosine kinase activity. In the intracellular domains of RET, 12 tyrosine (Y) autophosphorylation sites, Y687, Y806, Y809, Y826, Y900, Y905, Y981, Y1015, Y1029, Y1062, Y1090, and Y1096, have been identified by phosphorylation mapping and mass spectrometry, the first 10 of which are present in the common region of the three RET isoforms and the last two of which are present in only the long isoform [57, 58]. Of these autophosphorylation sites, several represent binding sites for a variety of docking proteins. Y1062 in the kinase domain is a binding site for SHC (Src-homology collagen), FRS2 (fibroblast growth factor receptor substrate 2), DOK1/4/5/6 (downstream of kinase 1/4/5/6), IRS1/2 (insulin receptor substrate
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Fig. 1 Intracellular signaling pathways mediated by RET. The “p” before amino acid residues means “phosphorylated”. PBM, POZ-binding motif
1/2), ShcC, PKCα (protein kinase Cα), and Enigma, and Y1062 phosphorylation activates multiple downstream signaling through the RAS/ERK (extracellular signal-regulated kinase), PI-3K (phosphatidylinositol-3-kinase)/AKT (v-akt murine thymoma viral oncoprotein homolog 1), p38MAPK (mitogen activated protein kinase), and Rac/JNK (c-jun Nterminal kinase) pathways (Fig. 1) [59–61]. These signals are important for cell survival, differentiation, proliferation, and motility. We recently demonstrated that DOK4, which binds phosphorylated RET Y1062, is required for GDNF-dependent neurite outgrowth, as reported in DOK5/6, through the downstream RAP1-ERK1/2 pathway with sustained ERK phosphorylation [62–64]. Two lines of studies using gene targeting in mice further demonstrated the importance of the signal through RET Y1062. RET knock-in mice generated by replacing the tyrosine residue of 1062 with phenylalanine (Y1062F) showed severe impairment of
enteric nervous system development and kidney hypoplasia [65]. Monoisoformic mice expressing only Ret9 with the Y1062F mutation, which were generated by inserting a cDNA encoding the intracellular part of Y1062 F-mutated Ret9 into exon 11 of the mouse RET locus in frame, showed severe kidney hypoplasia or dysplasia and lack of enteric ganglia in the caudal gastric region and throughout the intestine [66]. These findings indicate that the signal through RET Y1062 plays a crucial role in the histogenesis of the enteric nervous system and nephrogenesis in vivo. Y905, Y981, and Y1015 in the intracellular kinase domain and Y1096 in the C-terminal extended sequence represent binding sites for GRB7/10 (growth factor receptor-bound protein 7/10), c-Src/SH2-Bβ (Src homology 2-Bβ), PLCγ (phospholipase Cγ ), and GRB2, respectively (Fig. 1) [59–61]. The signal through phosphorylated RET Y981 and c-Src or SH2-Bβ promotes neuronal survival via a PI-3 K-dependent pathway Springer
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or GDNF-induced neurite outgrowth, respectively [67–69]. Phosphorylated Y1015 mediates activation of PLCγ , and phosphorylated Y1096, which is present only in the RET long isoform, mediates GRB2-dependent signaling. Both signals via Y1015 and Y1096 are required for the neoplastic properties of RET/PTC oncoproteins (described below) [70, 71]. Phosphorylation of Y687 in the juxtamembrane domain negatively regulates Rac-GEF (guanine nucleotide exchange factor) activity. Rac-GEF activity is also positively regulated by serine (S) 696, which is phosphorylated by PKA (protein kinase A) (Fig. 1) [72]. The balance of negative and positive regulation of Rac-GEF activity by phosphorylation of Y687 and S696 is responsible for lamellipodia formation [72]. Phosphorylation of Y806, Y809, and Y900 in the kinase domain is required for the kinase activity of RET, though their roles in intracellular signaling are obscure [58]. The significance of phosphorylation of Y826 in the kinase insert, Y1029 in the kinase domain, and Y1090 present in the long isoform-specific C-terminal sequence has not yet been elucidated. It should be noted that STAT3 (signal transducer and activator of transcription 3) binds to Y752 and Y928 in MEN 2A-mutated RET (described below) in a phosphorylationindependent manner and is an important downstream target of MEN 2A-mutated RET, being required for enhanced proliferation of cells expressing this protein (Fig. 1) [73]. Further, Shank3 (SH3 and multiple ankyrin repeat domains 3), a POZ (pox virus and zinc finger) domain-containing scaffolding adaptor protein that functions in the formation and maintenance of postsynaptic densities by integrating neurotransmitter receptors, binds specifically to the POZ-binding motif present in the RET9-specific C-terminal sequence [74]. Shank3 mediates sustained RAS/ERK and PI-3K/AKT signaling, which is crucial for renal tubule formation, suggesting a possible mechanism for biological divergence between the RET9 and RET51 isoforms [74]. Recent works indicated that lipid rafts, sphingolipid and cholesterol-rich microdomains in the plasma membrane are crucial for signal transduction of the GDNF-RET signaling pathway. It is well-known that GPI-anchored proteins are localized in lipid rafts. Accordingly, GFRα proteins are localized to lipid rafts, whereas the inactive form of RET is localized outside them. GDNF binds GFRα1 in lipid rafts and recruits RET to the rafts, triggering RET dimerization and phosphorylation; consequently, RET interacts with cSrc kinase and FRS2 docking protein in the lipid rafts. The phosphorylated RET can then move out from the lipid rafts and bind SHC outside them [75, 76]. Inhibition of RET recruitment to lipid rafts by their disruption using methyl-βcyclodextrin leads to abrogation of downstream signal activation and insufficiency of neuronal differentiation and survival [75]. Furthermore, RET can be activated in trans by GDNF and the soluble form of GFRα1, as well as in cis by Springer
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GDNF and membrane-anchored GFRα1 [76]. GDNF binds soluble GFRα1, and then the GDNF-GFRα1 complex triggers RET phosphorylation and activation outside lipid rafts, followed by translocation of the GDNF-GFRα1-RET complex into lipid rafts [75, 76]. Translocation of RET in the plasma membrane on GDNF stimulation enables activated RET to associate with different adaptor proteins inside and outside lipid rafts. More recently, Pierchala et al. showed that GDNF stimulation triggered not only phosphorylation of RET but also downregulation of RET expression, and that RET was ubiquitinated and degraded outside lipid rafts [77]. They proposed that lipid rafts sequester RET away from the degradation machinery located in the non-raft membrane domain, suggesting the importance of lipid rafts for RET physiological activities in cells [77]. Another interesting finding was reported by Richardson et al., who demonstrated that RET is internalized from the plasma membrane in a liganddependent manner that requires RET kinase activity as well as the GTPase activity of the clathrin-coated vesicle scission protein dynamin 2 [78]. They showed that RET co-localizes with the clathrin-coated vesicles after internalization, indicating an involvement of the clathrin-coated pit pathway in RET activities after GDNF stimulation. They also found that RET internalization is required for complete activation of ERK1/2, but not for activation of AKT signaling [78]. These two publications provide important suggestions about the physiological behavior of post-activated RET protein.
RET and neuroendocrine tumors RET and multiple endocrine neoplasia type 2 Neuroendocrine tumors arise from cells of neural crest origin with hormone secretion, so hormonal abnormalities are usually among their clinical features. In 1993, germline mutations in the RET proto-oncogene were first reported in patients with MEN 2A [11]. Now, it is apparent that RET is a causative gene of MEN 2A and MEN 2B, autosomal dominant neuroendocrine tumor syndromes, and their subtype, familial medullary thyroid carcinoma (FMTC) [11–13]. MEN 2A is characterized by the clinical features of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN 2B patients have a more complex phenotype including MTC with an earlier onset and more aggressive clinical course, pheochromocytoma, skeletal abnormalities, and mucosal neuroma, whereas FMTC is defined by the sole phenotype of MTC with a less aggressive clinical course without any other abnormalities. RET mutations in MEN 2A patients have been identified mainly in one of the six cysteine residues, 609, 611, 618, 620, 630, and 634, all of which reside in the extracellular cysteine-rich domain
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A
B S
FMTC
CA
G321 → R G533 → C R600 → Q K603 → E Y606 → C C609 → R C611 → Y, S C618 → S, R, Y C620 → R C630 → F C634 → Y, F, S
MEN 2A
CY TM
S649 → L E768 → D V777 → S Q781 → R L790 → F Y791 → F V804 → L I 852 → M S891 → A R912 → P
C609 → Y, S, R C611 → Y, S, G, W C618 → Y, S, R, F, G, C620 → Y, S, R, F, G C630 → F D631 → Y C634 → Y, S, R, F, G, W
Oncoprotein RET/PTC1: RET/PTC2: RET/PTC3: RET/PTC4: RET/PTC5: RET/PTC6: RET/PTC7: RET/PTC8: RET/PTC9: ELKS/RET: PCM1/RET: RFP/RET:
Fusion partner H4/D10S170 RIα of PKA
RFG5/golgin-84 hTIF1 GFG7/hTIFγ KTN1/kinectin RFG9 ELKS PCM1 RFP
Fusion partner
L790 →F S891 →A
TK
MEN 2B A833 →F M918→T
MEN 2 mutant RET
TK
RET intracellular domain
RET/PTC oncoprotein
Fig. 2. Distribution of mutations in RET identified in MEN 2A, MEN 2B, and FMTC (A), and a list of RET/PTC chimeric oncoproteins and their fusion partners with a scheme of RET/PTC oncoprotein structure
(B). S: signal sequence; CA: cadherin-related motif; CY: cysteine-rich region; TM: transmembrane domain; TK: tyrosine kinase domain
of RET (Fig. 2A) [61, 79]. Among these cysteine residues, codon 634 mutation is most frequently observed in MEN 2A patients (approximately 85%) [80, 81]. As a consequence, mutant RET is constitutively phosphorylated and activated, resulting in generation of oncogenic downstream signaling in cells, a so-called “gain-of-function” effect [82–89]. A possible molecular mechanism for RET activation by MEN 2A mutation is; substitution of a cysteine residue that is normally involved in intramolecular disulfide bond formation with an adjacent cysteine residue, causing disruption of this bond, and consequently, the remaining partner cysteine forms an intermolecular disulfide bond, resulting in RET dimerization and activation without ligand stimulation (Fig. 3B) [82, 83]. RET mutations in most MEN 2B patients are confined to substitution of methionine at codon 918 with threonine, or, in a few cases, substitution of alanine at codon 883 with phenylalanine (Fig. 2A) [61, 79]. These are also gain-of-function mutations leading to constitutive RET activation, the mechanism of which is assumed to be; a mutation at codon 918 or
883 in the intracellular tyrosine kinase domain that causes a conformational modification in the kinase domain, resulting in RET phosphorylation and activation without ligand stimulation in a monomeric form (Fig. 3C) [83–85]. It remains obscure how the differing phenotypes of MEN 2A and MEN 2B arise. We found that PI-3K/AKT and JNK phosphorylation was up-regulated in cells expressing MEN 2B-mutated RET compared with those expressing MEN 2Amutated RET [90, 91]. Furthermore, it was reported that JNK was highly activated in MEN 2B-mutated RET-expressing cells showing frequent metastasis in vivo [92]. Taken together with other studies on genotype-phenotype correlation in MEN 2, these results suggest that the substrate specificity of the two mutated RET proteins may lead to the difference of clinical phenotypes between MEN 2A and MEN 2B [93–96]. AKT is known to be involved in promoting cell proliferation, survival, and motility, and tumors with high AKT expression show aggressive clinical behavior [97, 98]. We recently identified an actin-binding protein, Girdin, as a new AKT substrate [99]. Girdin is localized on stress fibers in Springer
184 Fig. 3. Mechanisms of RET activation. A: GDNF-dependent RET activation. B: MEN 2A-mutated RET activation. C: MEN 2B-mutated RET activation. D: Activation of RET/PTC chimeric oncoprotein. X indicates the position of mutation
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A. Wild type RET
B. MEN 2A
C. MEN 2B
D. RET/PTC
GFLs C
×
C
×
GFRαs
Fusinon partenr
P Y
Y P
P Y
Y P
P Y
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P Y
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quiescent cells, and on AKT activation, phosphorylated Girdin accumulates at the leading edge of migrating cells. Mutant Girdin-expressing cells formed abnormal shapes and exhibited limited migration and lamellipodia formation, suggesting that Girdin plays a crucial role in the formation of stress fibers and lamellipodia, and provides a direct link between AKT and cell motility [99]. Thus, it is possible that the PI-3K/AKT/Girdin signaling pathway is closely associated with the aggressive behavior of MEN 2B-associated MTC. It is interesting that two gene expression studies using differential display and microarray technologies identified several genes highly expressed in cells expressing MEN 2B-mutated RET or MTC in MEN 2B patients, including stanniocalcin-1 and chondromodulin-1, which are known to be involved in calcium/phosphate homeostasis and the regulation of cartilage and bone growth [100, 101]. Furthermore, genes associated with the TGFβ pathway were found to be up-regulated in MEN 2B-associated MTC, providing a clue to the molecular mechanisms of MEN 2B phenotype development [101]. RET mutations in FMTC families are reported at codons 321, 533, 600, 603, 606, 609, 611, 618, 620, 630, 634, 649, 768, 777, 778, 781, 790, 791, 804, 852, 891, and 912, overlapping at several codons with those in MEN 2A patients (Fig. 2A) [61, 79]. FMTC RET mutations are gain-offunction mutations causing phosphorylation and activation of RET protein without ligand stimulation, as well as MEN 2A or MEN 2B RET mutations. The difference of clinical features between FMTC and MEN 2 seems to depend on the oncogenic activity of the mutated RET proteins, though less is known about the activity in vivo [89]. Recently, several publications mentioned that some FMTC RET mutations other than classical MEN 2A mutations in the cysteine-rich Springer
×
Y P Y P
P Y
Y P
P Y
Y P
domain have a potential to develop MEN 2A [102, 103]. In addition, some rare mutations in RET genes were reported in MEN 2 A patients [61, 104–106]. Thus, further genetic and clinical evidence, including long follow-up data from MTC patients with RET mutations, needs to be assessed to elucidate the correlation between MEN 2 phenotypes and rare mutations in RET. Sporadic medullary thyroid carcinoma Approximately 75% of MTC cases are sporadic, and somatic RET mutations have been identified in 23–69% of patients with sporadic MTC [107–109]. Somatic RET mutations at codons 591, 630, 634, 639, 641, 748, 766, 768, 883, 876, 884, 901, 908, 911, 918, 919, 921, 922, and 930 and small deletions including codons 630 and 634 have been reported in sporadic MTC patients [106, 110–117]. Interestingly, somatic mutation at codon 918, which is the most common position of germline mutations in MEN 2B patients, is the most predominant in sporadic MTC patients and is correlated with poor prognosis, suggesting strong carcinogenecity of codon 918 mutations [114, 118]. Germline mutations, including de novo mutations, are also observed in clinically apparent sporadic MTC (9–25%), indicating that some sporadic MTCs are undetected inherited MTCs [112, 119–125]. Sporadic pheochromocytoma Pheochromocytoma is a tumor derived from chromaffin cells secreting catecholamines. The tumor develops mainly in the adrenal medulla but also in the extra-adrenal paraganglia of the abdomen, and most are sporadic [126]. However,
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recent accumulating evidence suggests that hereditary-based pheochromocytoma is more frequent than previously thought [127–129]. At present, germline mutations in six genes have been identified in pheochromocytoma patients: the RET gene susceptible for MEN 2, the VHL gene for von Hippel–Lindau Disease, the NF1 gene for von Recklinghausen’s neurofibromatosis, and the SDHB, SDHC, and SDHD (succinate dehydrogenase subunits B, C and D) genes for paragangliomapheochromocytoma syndrome [127, 128, 130–132]. Neumann et al. reported that 66 (24%) out of 271 patients with clinically sporadic pheochromocytoma had germline mutations in one of the RET, VHL, SDHB, and SDHD genes, and nearly half of the affected patients had mutations in the VHL gene [127]. RET germline mutations were observed in 13 (5%) patients in this population with sporadic pheochromocytoma, and all cases with RET mutations had adrenal pheochromocytoma. The affected codons were cysteine at 634 (12 patients) and tyrosine at 791 (one patient), both of which are associated with MEN 2A/FMTC development, and most of the patients with RET germline mutations developed MTC during the follow-up period, indicating that clinically apparent sporadic pheochromocytomas associated with RET germline mutations might be part of undiagnosed MEN 2 [127]. Somatic RET mutations have also been detected in 0– 31% of patients with sporadic pheochromocytoma, mostly at codon 918 [133–135].
RET and papillary thyroid carcinoma Papillary thyroid carcinomas (PTCs) originate from thyroid follicular cells without hormone secretion, so they are not neuroendocrine tumors. However, because RET is closely associated with the pathogenesis of PTC, we briefly summarize its involvement in PTC development. PTC is the most common thyroid malignancy (85–90% of all malignant thyroid tumors) and is diagnosed by the histological pattern and distinct nuclear features [136]. Somatic RET rearrangements have been detected in 13–44% of sporadic and 50–90% of radiation-associated PTC, in which the RET intracellular kinase domain is fused to other proteins by chromosomal inversion or translocation, resulting in generation of chimeric oncoproteins (RET/PTCs) (Fig. 2B) [136–143]. RET expression is normally observed in limited cells such as the calcitonin-producing C-cells but not the follicular cells in the thyroid gland. On somatic rearrangement, RET/PTCs, which possess non-RET sequences in the N-terminal region, are expressed under the control of promoters of the rearranged partners, leading to RET/PTC expression in follicular cells. To date, 12 RET/PTC rearranged forms have been reported in sporadic and radiationassociated PTC: RET/PTC1 − 9, ELKS/RET, PCM1/RET, and RFP/RET (Fig. 2B) [61, 138, 139]. Because all of the
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chimeric partner proteins have domains for dimerization, such as coiled-coil motifs, the RET/PTC protein is assumed to be phosphorylated and activated by forming a homodimer via the partner protein in the cytoplasm, resulting in constitutive activation of downstream signaling (Fig. 3D). Recently, mutations in the BRAF gene were identified in sporadic PTC [144–147]. BRAF is a serine/threonine kinase and constitutes a signaling cascade with RET/PTC and RAS (RET/PTC-RAS-BRAF cascade) in which RET/PTC induces ERK activation [148, 149]. Activating BRAF mutations are found in about 45% of sporadic PTCs, and 66% of sporadic PTCs have a RET/PTC rearrangement or a mutation in BRAF or RAS, indicating a greater involvement of the RET/PTC-RAS-BRAF pathway in the development of sporadic PTC [144, 147].
Management of MEN 2 Since MTC is a major life-threatening disease with a high penetrance in MEN 2 carriers, appropriate diagnosis and treatment are important in their management. MTCs in MEN 2B patients tend to develop earlier and progress more aggressively than those in MEN 2A and FMTC patients; thus, success in prevention or cure of MTC is mainly dependent on an adequate initial operation. A consensus was reached at the Sixth International Workshop on Multiple Endocrine Neoplasia that the decision to perform thyroidectomy in MEN 2 should be based predominantly on the result of RET mutation testing, rather than on calcitonin testing [150]. Since RET mutations are identified in 98% of MEN 2 patients in a limited region of the RET sequence, DNA-based molecular testing is an easy and accurate way to diagnose MEN 2 carriers [151, 152]. Considering the clinical benefit of finding MEN 2 carriers, all cases of sporadic MTC or pheochromocytoma should be tested for germline mutations in RET, as well as relatives of MEN 2 patients. An international group published a guideline for the diagnosis and therapy of MEN 2 indicating that only RET exons 10, 11, 13, 14, 15, and 16 must be tested routinely for carrier screening [153]. If these are negative, the remaining 15 exons should be sequenced. Based on the information of RET mutation, carrier children are classified into three levels of risk of MTC for thyroid management. Children with MEN 2B-associated RET mutation are classified as level 3, or as having the highest risk for aggressive MTC, and should have thyroidectomy including central node dissection within the first 6 months and preferably within the first month of life. Children with RET codon 611, 618, 620, or 634 mutation are classified as level 2, or as having a high risk for MTC, and should have thyroidectomy including removal of the posterior capsule before the age of 5 years. Children with RET codon 609, 768, 790, 791, 804, or 891 mutation are classified as level 1, or as Springer
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having the least high risk, and should also have total thyroidectomy [153]. Patients with other, newly identified RET mutations should be included in level 1. Recently, evaluations of the clinical outcome of prophylactic thyroidectomy in MEN 2 carriers were reported by several groups [154– 159]. Histopathological assessment revealed that MTC or C-cell hyperplasia was found in most thyroidectomy specimens from presymptomatic carriers, suggesting the necessity of early diagnosis and thyroidectomy. In addition, a lower incidence of persistent or recurrent disease was shown in children who underwent prophylactic thyroidectomy at an early age, indicating that prophylactic thyroidectomy is effective in the management of MEN 2 carriers [154–159]. The life-threatening event associated with pheochromocytoma is a hypertensive crisis arising from an unsuspected pheochromocytoma, causing sudden death. Since pheochromocytoma usually becomes evident about 10 years later than C-cell hyperplasia or MTC in MEN 2 patients, this issue can be addressed by routine screening for pheochromocytoma by measurement of plasma metanephrines or urinary catecholamines or metanephrines. Screening should begin at the age of thyroidectomy in MEN 2 patients with a high-risk RET mutation such as codon 634 [153]. Prophylactic surgery for pheochromocytoma is unusual in MEN 2 patients. The aim of pheochromocytoma management is to prevent sudden death and cardiovascular complications. Parathyroid hyperplasia occurs in 20–30% of MEN 2A patients and causes primary hyperparathyroidism with elevation of serum parathyroid hormone. Germline RET mutation at codon 634 is highly associated with the development of parathyroid hyperplasia in MEN 2A patients [157]. Most cases have no symptoms or mild clinical features of hypercalciuria and renal calculi. Management of parathyroid hyperplasia in MEN 2A patients, including the diagnostic criteria and surgical intervention, is similar to that in patients with sporadic primary hyperparathyroidism [161, 162]. As there is no effective chemotherapeutic regimen for advanced MTC at present, and metastatic MTC is not very sensitive to X-ray or thermal radiation therapy [153, 163, 164], several trials to find a new approach for treatment of advanced MTC in MEN 2 and RET-associated PTC are in progress, with RET as a molecular target. Imatinib (STI571), a tyrosine kinase inhibitor currently used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors with constitutively activated BCR/ABL and KIT tyrosine kinase, respectively, has been reported to inhibit RET Y1062 phosphorylation and cell proliferation in MTC cell lines with mutant RET expression [165–168]. The other tyrosine kinase inhibitors, SU11248 (sunitinib malate), BAY 43– 9006 (sorafenib), 4-anilinoquinazoline ZD6474, arylidene 2-indolinone RPI-1, pyrazolopyrimidines PP1 and PP2, and indolocarbazole derivatives CEP-701 and CEP-751, have the potential to inhibit RET activation and cell growth or induce Springer
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apoptosis in cells expressing oncogenic mutant RET [169– 178]. Although most of these tyrosine kinase inhibitors are still under investigation, their powerful effects may offer a promising new approach to management of RET-associated malignancies.
Conclusions Research on the RET proto-oncogene associated with neuroendocrine tumors is gradually moving from bench to bedside. Many researchers and clinicians have contributed to the progress of studies on RET since 1985 and have established a consensus for each process: (1) identification and characterization of the RET proto-oncogene, (2) analyses of RET physiological function, (3) assessment of RET alterations in neuroendocrine tumors, (4) elucidation of the mechanisms of RET-associated tumor development, (5) application of RET to genetic testing of RET-associated tumors, and (6) application of the RET genotype to surgical treatment. However, despite recent marked advances in the management of presymptomatic carriers and some MTC patients, effective treatment for advanced MTC is still under investigation. Furthermore, it remains unclear what kind of mechanism underlies the clinical differences between MEN 2A and MEN 2B. Further intensive research for the elucidation of wildtype RET function as well as mutant RET oncogenecity may enable better management of MEN 2 patients including medication therapy for advanced MTC in the near future.
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