RET point mutations in Thyroid Carcinoma

 

Rossella Elisei, Cristina Romei, Barbara Cosci, Eleonora Molinaro, Laura Agate, Valeria Bottici, Aldo Pinchera

Department of Endocrinology and Metabolism University of Pisa, Pisa, Italy

 

April 2008

 

 

RET structure and function

The human RET gene maps on 10q11.2 and is composed by 21 exons with an estimated size of about 55 kb (Pasini et al., 1995). The RET gene encodes for a tyrosine kinase transmembrane receptor (Takahashi et al., 1988) characterized by 3 different domains: a) the extracellular domain, which contains the signal peptide, the cadherin-like region and the cysteine-rich region; b) the transmembrane domain; c) the intracellular portion containing the tyrosine kinase domain. RET is expressed in a variety of neuronal cell lineages including thyroid C cells and adrenal medulla. Although still debated, recently it has been reported that RET gene expression may also occur in follicular thyroid cells (Fludge et al., 2001).
The physiological ligands of RET belong to the glial derived neurotrophic factors (GDNFs) family. Four members of this family, neurturin, persephin, artemin and GDNF, have a specific trophic effect on RET (Robertson and Mason, 1997). The activation of RET is mediated by the interaction of the ligands with 4 co-receptors, GFRα1, 2, 3 and 4 (Jing et al., 1996; Treanor et al., 1996; Trupp et al., 1996; Klein et al., 1997; Buj-Bello et al., 1997; Milbrandt et al., 1998; Baloh et al., 1998). RET dimerization is the natural consequence of the formation of the ligand-coreceptor-receptor complex and is responsible for the activation of the kinase catalytic domain and of the signal transduction which induces cells proliferation through a complex network of second messengers (Marshall, 1995). The oncogenic transformation of RET gene determines a constitutive activation of the receptor itself with the consequent induction of an uncontrolled cell proliferation and tumoral development (Fig. 1).

The oncogenic activation of RET in medullary thyroid carcinoma (MTC) occurs mainly through the substitutiton of a single nucleotide. The nature of the RET mutations determines the molecular mechanisms of its oncogenic activation. RET mutations involving the cystein reach region promote RET homodimerization via the formation of intermolecular disulfide bounds (Marshall, 1995; Santoro et al., 1995). Mutations affecting the region of RET coding for the intracellular catalytic portion appears to modify the substrate specificity of the tyrosine kinase activity leading to the constitutive activation of the receptor ( Santoro et al., 1995; Songyang et al., 1995).

RET mutations in Multiple Endocrine Neoplasia type 2 (MEN 2)

MEN 2 is an autosomal dominant inherited disease characterized by the presence of MTC plus other endocrine tumors: pheochromocytoma (PHEO) and/or parathyroid adenomas (hyperPTH) in MEN 2A, PHEO and mucosal neurinomas in MEN 2B. MTC alone, lacking the association with other endocrine tumors, may also be inherited (FMTC) (Keiser et al., 1973; Cunliffe et al., 1970; Farndon et al. 1986). In these syndromes, MTC develops in nearly 100% of the affected individuals, while PHEO and hyperPTH develop in around 50% and 20% respectively.
In 1993 two independent groups discovered that germline point mutations of the RET proto-oncogene are causative events in MEN 2A (Mulligan et al., 1993) and in FMTC (Donis-Keller et al., 1993). One year later, also MEN 2B was associated with germline point mutations of the RET proto-oncogene (Eng et al., 1994; Carlson et al., 1994; Hofstra et al., 1994). Since then, a large number of publications have addressed the relationship between RET mutations and the clinical phenotype of MEN 2 patients and the clinical implication of screening MEN 2 family members for RET gene mutations. The most comprehensive study correlating the genotype to the phenotype of MEN 2 patients was published in 1996 by the International RET Mutation Consortium (Eng et al., 1996), which reported the results of a large cooperative survey including 477 pedigrees screened for the presence of germline RET proto-oncogene mutations. Germline RET point mutations were found in 92% of the whole group, including 95% of 79 families with MEN 2B, 98.0% of 203 families with MEN 2A and 88% of 34 families with FMTC. A specific mutation in exon 16, at codon 918 (ATG to ACG) was invariably associated with MEN 2B. In MEN 2A, several different cystein codons in exon 10 and 11 were affected, but codon 634 mutations were by far the most common, accounting for 85% of the cases. This mutation (mainly TGC to CGC) was also found to correlate significantly with the presence of PHEO and hyperPTH. In FMTC, the mutations were almost evenly distributed among the 5 cysteine codons 609, 611, 618, 620 and 634. Interestingly, mutations in the cystein rich domain (codons 609, 611, 618 and 620) are not only found in families with MEN 2A/FMTC but also in patients with Hirschprung’s disease, a congenital malformation characterized by an absence of enteric galglia cells in the distal part of the colon, or patients having a combination of MEN 2 and Hirschprung’s disease (Arighi et al., 2004; Takahashi et al., 1999; Sijmons et al., 1998).
The number and type of RET mutations have been grown over the last 10 years, especially after the introduction of RET genetic screening in the work up of all patients with MTC, both hereditary and apparently sporadic. As consequence of this more careful research, RET mutations have been found to be widely distributed not only among the 5 cysteine codons but also in other non-cysteine codons, such as codon 804 in exon 14, codon 883 and codon 891 in exon 15 and others (Jimenez et al., 2004; Niccoli-Sire et al., 2001). These widely spread mutations are mainly associated with FMTC phenotype (Niccoli-Sire et al., 2001; Elisei et al., 2007). Large series of MTC hereditary cases have shown a significant correspondence between specific RET mutations and both phenotype and the level of aggressiveness of the MTC tumor (Elisei et al., 2007; Machens et al., 2003; Machens et al., 2007; Frank-Raue et al., 2008; Machens et al., 2003) (Fig 2).

In particular M918T has been recognized as the most aggressive one, as demonstrated by the evidence that the majority of patients with this germline mutation (ie MEN 2B) usually die at young age while, at variance, mutations like Y791F (Frank-Raue et al., 2008) and A883T (Elisei et al., 2004) could never develop into MTC. The correlation between the type of mutation and the aggressiveness of the MTC has been confirmed also by several in vitro studies showing different degree of tumoral transforming activity (Carlomagno et al., 1997; Chappuis-Flament et al., 1998; Mise et al., 2006).
In about 4-10% of MEN 2A or FMTC patients and in about 95% of those with MEN 2B the germline RET mutation is a “de novo” mutation as demonstrated by the negative finding of the RET genetic analysis in the patients’ parents. In these cases the mutation is usually located in the allele inherited from the patient’s father (Schuffenecker et al., 1997).

Clinical implication of RET genetic screening

The clinical implications of RET mutations in MEN 2 is the possibility to screen family members to find those who harbour the same germline mutation previously detected in a MTC index case. This allows the identification of the “gene carriers” when they are clinically unaffected or at an early stage of the disease, and to exclude “non gene carriers” from further testing for the rest of their life. Several series have confirmed the effectiveness of this approach. Gene carriers have been detected with a frequency ranging from 15.5% and 69.0% (Elisei et al;, 2007; Pacini et al., 1995; Lips et al., 1994; Frilling et al., 1995; Frank-Raue et al., 1997; Skinner et al., 2005), in almost every decade of life, but more frequently at very young age.
Once a gene carrier is found, he/she must undergo clinical and biochemical examination to assess the presence or absence of clinical or pre-clinical disease. This includes screening of MTC by neck palpation, neck ultrasound and measurement of basal and pentagastrin-stimulated serum calcitonin, screening for hyperPTH by measurement of serum calcium and parathyroid hormone, and screening for PHEO by measurement of plasma or urinary cathecolamines. Since MTC is usually the first clinical manifestation of the disease, it is very rare to find no evidence of MTC in the presence of hyperPTH or/and PHEO. Nevertheless, screening for these conditions is mandatory to avoid the risk of surgical procedures in patients with undiagnosed PHEO. Whenever clinical or biochemical (elevated basal and/or pentagastrin-stimulated serum calcitonin) evidences of MTC are found, surgery is the treatment of choice. In this situation, the surgical procedure should be the same applied to any patient presenting with clinical MTC, i.e. total thyroidectomy and lymph node dissection. When a gene carrier is detected before the onset of clinical and biochemical manifestations, the decision of performing a prophylactic total thyroidectomy must be weighted against the possible morbidity of this procedure.
On the other hand, it is well known that permanent cure of MTC is only achieved when surgery is performed at an early stage, when the tumor is intrathyroidal. This has been demonstrated in old studies using biochemical screening programs (Wolfe et al., 1973) and more recently in several series of subjects operated on the basis of positive genetic screening (Lips et al., 1994; Pacini et al., 1994; Dralle et al., 1998). C-cell hyperplasia, a pre-malignant lesion, has been found by Gagel et al. (Gagel et al., 1995) in 4 children operated on the basis of a germline RET mutation, one of whom had microscopic MTC in addition. Out of 7 patients (7-28 years of age) treated by Learoyd et al (Learoyd et al., 1997) 3 had MTC and 4 had C-cell hyperplasia. In a series by Wells et al. (Wells et al., 1994), 13 of 21 family members carrying RET gene mutation were treated by surgery, including 6 with normal plasma calcitonin. Their age ranged from 6-20 years. All had C-cell hyperplasia with or without MTC. No patient had lymph node metastases and the post-operative stimulated plasma calcitonin was normal in all.
The practical recommendation that can be derived from the above considerations is that family members at-risk of hereditary MTC should be screened by genetic analysis as early as possible, to distinguish those with or without RET mutation. The last can be reassured on their status and relieved from further follow-up. Those with the mutation should be considered for total thyroidectomy. The timing of surgery may change according to the results of the clinical and biochemical screening. In the presence of clinical or biochemical evidence of MTC, surgery will immediately be performed. If no evidence of disease is found, it is possible to go on with a prophylactic thyroidectomy, or to delay surgery while monitoring the calcitonin response to pentagastrin.

RET screening in patients presenting with apparently sporadic MTC

Screening sporadic MTCs for germline RET mutations may help in differentiating patients truly sporadic from those with unrecognized hereditary disease. The benefit of this procedure is evident for both the affected patients and their relatives, and for the unaffected patients. If an unexpected germline RET mutation is found the physician will be alerted on the possible coexistence or future development of adrenal or parathyroid disease. The screening may be extended to his/her first degree relatives, thus detecting additional gene carriers, usually in the preclinical phase of the disease. On the other hand, the negative germline RET mutated patient can be reassured on the sporadic nature of the disease, thus avoiding the need to screen his/her relatives.
The frequency of germline RET mutations in apparently sporadic cases ranges between 1.5% and 22.7% in different series (Schuffenecker et al., 1997; Decker et al., 1995; Eng et al., 1995; Wohllk et al., 1996; Komminoth et al., 1995; Chiefari et al., 1998; Shirahama et al., 1998). In our series, 39 out of 485 patients (8%) presenting as sporadic cases, had a germline mutation in their constitutive DNA (Elisei et al., 2007). Five were MEN 2A (one “de novo”) and 34 were FMTC. Their recognition allowed the discovery of 45 additional family members carryng the mutation, unaware of their status. The systematic analysis of RET mutations in apparently sporadic MTC allowed us to identify 5 mutations never described up to now (A883T, M918V, S904F, V648I, M848T). In particular the A883T mutations was found associated to MTC only in its homozygous state (Elisei et al., 2004).
Screening of sporadic MTCs is better accomplished if the tumoral DNA is firstly tested. In case that a somatic RET mutation is found, the same mutation is searched in the blood DNA to ascertain whether the mutation is indeed an unexpected germline mutation. In this case the hereditary nature of the disease is certain. If not, the tumor is sporadic. In case that no mutation is found in the tumoral tissue, blood DNA analysis is not required: the case is very likely to be sporadic, although the existence of MEN 2 families in which the germline mutation is not found is reported in any series. An algorithm of the steps to follow for the RET genetic screening in apparently sporadic MTC is illustrated in Fig 3.

Somatic mutations of the RET proto-oncogene are found in sporadic MTC, with a frequency ranging from 23% to 70% (Eng et al., 1994; Hofstra et al., 1994; Elisei et al., 2007; Romei et al., 1996; Zedenius et al., 1994; Eng et al., 1995; Blaugrund et al., 1994). In most cases the mutation is a MEN 2B-like M918T mutation, but other codons may be involved (Eng et al., 1994; Eng et al., 1995). In addition to point mutations, a few cases of somatic gene deletions have been reported (Elisei et al., 2007; Romei et al., 1996; Ceccherini et al. 1997). Somatic RET point mutations are also found in nearly 10% of sporadic PHEO (Eng et al., 1994; Romei et al., 1996; Beldjord et al., 1995; Lindor et al., 1995; Eng et al., 1995) but not in hyperPTH ( Romei et al., 1996; Padberg et al., 1995; Pausova et al. 1996; Uchino et al., 2000).

Few years ago, a correlation between the presence of a somatic RET mutation and a more aggressive phenotype of the sporadic MTC was reported by several groups (Romei et al., 1996; Zedenius et al., 1998; Zedenius et al., 1995; Schilling et al., 2001). We recently provided the evidence that MTC patients with a somatic RET mutation not only have a greater probability of unsuccessful treatment, but that they have a higher probability of dying from the disease, as demonstrated by their significantly worse 30-year survival rate with respect to that of patients without somatic RET mutations (Elisei et al., 2007).

Conclusions

Since 1993, year in which RET oncogene was demonstrated to be the causative event for MTC, several mutations have been described in MEN2 series and new mutations still continue to be discovered. A strict correlation between the type of mutation and the disease phenotype has been largely demonstrated in several studies during the last years and the RET genetic screening has been revealed as a very important diagnostic procedure for hereditary MTC. Finally RET somatic mutations have been shown to be an important bad prognostic indicator for sporadic MTC. For these reasons it appears evident that RET genetic screening is of great clinical relevance for its well established diagnostic and prognostic role. The possibility to employ new targeted therapy directed against RET mutated protein is the challenge of the near future and several tyrosine kinase inhibitors are under investigation in clinical trials (Schlumberger et al., 2008).

Bibliography

A calcitonin-secreting medullary thyroid carcinoma associated with mucosal neuromas, marfanoid features, myopathy and pigmentation.

Cunliffe WJ, Hudgson P, Fulthorpe JJ, Black MM, Hall R, Johnston ID, Shuster S.

Am J Med. 1970 Jan;48(1):120-6.

PMID 5415403

Sipple's syndrome: medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Studies in a large family. NIH conference.

Keiser HR, Beaven MA, Doppman J, Wells S Jr, Buja LM.

Ann Intern Med. 1973 Apr;78(4):561-79.

PMID 4632792

C-cell hyperplasia preceding medullary thyroid carcinoma.

Wolfe HJ, Melvin KE, Cervi-Skinner SJ, Saadi AA, Juliar JF, Jackson CE, Tashjian AH Jr.

N Engl J Med. 1973 Aug 30;289(9):437-41.

PMID 4587234

Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity.

Farndon JR, Leight GS, Dilley WG, Baylin SB, Smallridge RC, Harrison TS, Wells SA Jr.

Br J Surg. 1986 Apr;73(4):278-81.

PMID 3697657

Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.

Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H.

Oncogene. 1988 Nov;3(5):571-8.

PMID 3078962

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr.

Hum Mol Genet. 1993 Jul;2(7):851-6.

PMID 8103403

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al.

Nature. 1993 Jun 3;363(6428):458-60.

PMID 8099202

RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer.

Blaugrund JE, Johns MM Jr, Eby YJ, Ball DW, Baylin SB, Hruban RH, Sidransky D.

Hum Mol Genet. 1994 Oct;3(10):1895-7.

PMID 7849720

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA Jr, Goodfellow PJ, Donis-Keller H.

Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1579-83.

PMID 7906417

Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.

Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A, et al.

Hum Mol Genet. 1994 Feb;3(2):237-41.

PMID 7911697

A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, et al.

Nature. 1994 Jan 27;367(6461):375-6.

PMID 7906866

Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A.

Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, van Gils AP, de Wit MJ, Zewald RA, Berends MJ, et al.

N Engl J Med. 1994 Sep 29;331(13):828-35.

PMID 7915822

Treatment of preclinical medullary thyroid carcinoma in MEN 2A gene carrier.

Pacini F, Martino E, Romei C, Ceccherini I, Basolo F, Iacconi P, Pinchera A.

Lancet. 1994 Oct 15;344(8929):1084-5.

PMID 7934463

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

Wells SA Jr, Chi DD, Toshima K, Dehner LP, Coffin CM, Dowton SB, Ivanovich JL, DeBenedetti MK, Dilley WG, Moley JF, et al.

Ann Surg. 1994 Sep;220(3):237-47; discussion 247-50.

PMID 7916559

Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC:s.

Zedenius J, Wallin G, Hamberger B, Nordenskjold M, Weber G, Larsson C.

Hum Mol Genet. 1994 Aug;3(8):1259-62.

PMID 7987299

The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects.

Beldjord C, Desclaux-Arramond F, Raffin-Sanson M, Corvol JC, De Keyzer Y, Luton JP, Plouin PF, Bertagna X.

J Clin Endocrinol Metab. 1995 Jul;80(7):2063-8.

PMID 7608256

Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete?

Decker RA, Peacock ML, Borst MJ, Sweet JD, Thompson NW.

Surgery. 1995 Aug;118(2):257-63; discussion 263-4.

PMID 7638742

Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas.

Eng C, Crossey PA, Mulligan LM, Healey CS, Houghton C, Prowse A, Chew SL, Dahia PL, O'Riordan JL, Toledo SP, et al.

J Med Genet. 1995 Dec;32(12):934-7.

PMID 8825918

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, Neumann HP, Ponder MA, Ponder BA.

Clin Endocrinol (Oxf). 1995 Jul;43(1):123-7.

PMID 7641404

Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma.

Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, Neumann HP, Pfragner R, Behmel A, Lorenzo MJ, et al.

Genes Chromosomes Cancer. 1995 Mar;12(3):209-12.

PMID 7536460

Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

Frilling A, Dralle H, Eng C, Raue F, Broelsch CE.

Surgery. 1995 Dec;118(6):1099-103; discussion 1103-4.

PMID 7491529

Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A.

Gagel RF, Cote GJ, Martins Bugalho MJ, Boyd AE 3rd, Cummings T, Goepfert H, Evans DB, Cangir A, Khorana S, Schultz PN.

J Intern Med. 1995 Oct;238(4):333-41.

PMID 7595169

Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas.

Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU.

Cancer. 1995 Aug 1;76(3):479-89.

PMID 8625130

Mutations in the RET protooncogene in sporadic pheochromocytomas.

Lindor NM, Honchel R, Khosla S, Thibodeau SN.

J Clin Endocrinol Metab. 1995 Feb;80(2):627-9.

PMID 7852530

Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation.

Marshall CJ.

Cell. 1995 Jan 27;80(2):179-85.

PMID 7834738

Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland.

Padberg BC, Schroder S, Jochum W, Kastendieck H, Roth J, Heitz PU, Komminoth P.

Am J Pathol. 1995 Dec;147(6):1600-7.

PMID 7495285

The physical map of the human RET proto-oncogene.

Pasini B, Hofstra RM, Yin L, Bocciardi R, Santamaria G, Grootscholten PM, Ceccherini I, Patrone G, Priolo M, Buys CH, et al.

Oncogene. 1995 Nov 2;11(9):1737-43.

PMID 7478601

Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations.

Pacini F, Romei C, Miccoli P, Elisei R, Molinaro E, Mancusi F, Iacconi P, Basolo F, Martino E, Pinchera A.

Surgery. 1995 Dec;118(6):1031-5.

PMID 7491519

Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B.

Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, et al.

Science. 1995 Jan 20;267(5196):381-3.

PMID 7824936

Catalytic specificity of protein-tyrosine kinases is critical for selective signalling.

Songyang Z, Carraway KL 3rd, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, et al.

Nature. 1995 Feb 9;373(6514):536-9.

PMID 7845468

Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas.

Zedenius J, Larsson C, Bergholm U, Bovee J, Svensson A, Hallengren B, Grimelius L, Backdahl M, Weber G, Wallin G.

J Clin Endocrinol Metab. 1995 Oct;80(10):3088-90.

PMID 7559902

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Mulligan LM, et al.

JAMA. 1996 Nov 20;276(19):1575-9.

PMID 8918855

GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.

Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM.

Cell. 1996 Jun 28;85(7):1113-24.

PMID 8674117

Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2.

Pausova Z, Soliman E, Amizuka N, Janicic N, Konrad EM, Arnold A, Goltzman D, Hendy GN.

J Clin Endocrinol Metab. 1996 Jul;81(7):2711-8.

PMID 8675600

Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence.

Romei C, Elisei R, Pinchera A, Ceccherini I, Molinaro E, Mancusi F, Martino E, Romeo G, Pacini F.

J Clin Endocrinol Metab. 1996 Apr;81(4):1619-22.

PMID 8636377

Characterization of a multicomponent receptor for GDNF.

Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock RA, Hefti F, Phillips HS, Goddard A, Moore MW, Buj-Bello A, Davies AM, Asai N, Takahashi M, Vandlen R, Henderson CE, Rosenthal A.

Nature. 1996 Jul 4;382(6586):80-3.

PMID 8657309

Functional receptor for GDNF encoded by the c-ret proto-oncogene.

Trupp M, Arenas E, Fainzilber M, Nilsson AS, Sieber BA, Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Arumae U.

Nature. 1996 Jun 27;381(6585):785-9.

PMID 8657281

Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

Wohllk N, Cote GJ, Bugalho MM, Ordonez N, Evans DB, Goepfert H, Khorana S, Schultz P, Richards CS, Gagel RF.

J Clin Endocrinol Metab. 1996 Oct;81(10):3740-5.

PMID 8855832

Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase.

Buj-Bello A, Adu J, Pinon LG, Horton A, Thompson J, Rosenthal A, Chinchetru M, Buchman VL, Davies AM.

Nature. 1997 Jun 12;387(6634):721-4.

PMID 9192899

The different RET-activating capability of mutations of cysteine 620 or cysteine 634 correlates with the multiple endocrine neoplasia type 2 disease phenotype.

Carlomagno F, Salvatore G, Cirafici AM, De Vita G, Melillo RM, de Franciscis V, Billaud M, Fusco A, Santoro M.

Cancer Res. 1997 Feb 1;57(3):391-5.

PMID 9012462

Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET proto-oncogene.

Ceccherini I, Pasini B, Pacini F, Gullo M, Bongarzone I, Romei C, Santamaria G, Matera I, Mondellini P, Scopsi L, Pinchera A, Pierotti MA, Romeo G.

Oncogene. 1997 May 29;14(21):2609-12.

PMID 9191060

Mutations of ret-proto-oncogene in thyroid medullary carcinoma

Frank-Raue K, Hoppner W, Buhr H, Herfarth C, Ziegler R, Raue F.

Dtsch Med Wochenschr. 1997 Feb 7;122(6):143-9.

PMID 9081799

A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.

Klein RD, Sherman D, Ho WH, Stone D, Bennett GL, Moffat B, Vandlen R, Simmons L, Gu Q, Hongo JA, Devaux B, Poulsen K, Armanini M, Nozaki C, Asai N, Goddard A, Phillips H, Henderson CE, Takahashi M, Rosenthal A.

Nature. 1997 Jun 12;387(6634):717-21.

PMID 9192898

Genetic testing for familial cancer. Consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2.

Learoyd DL, Marsh DJ, Richardson AL, Twigg SM, Delbridge L, Robinson BG.

Arch Surg. 1997 Sep;132(9):1022-5.

PMID 9301617

The GDNF-RET signalling partnership.

Robertson K, Mason I.

Trends Genet. 1997 Jan;13(1):1-3.

PMID 9009838

Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine.

Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, Houdent C, Pallo D, Schlumberger M, Thivolet C, Lenoir GM.

Am J Hum Genet. 1997 Jan;60(1):233-7.

PMID 8981969

Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex.

Baloh RH, Tansey MG, Lampe PA, Fahrner TJ, Enomoto H, Simburger KS, Leitner ML, Araki T, Johnson EM Jr, Milbrandt J.

Neuron. 1998 Dec;21(6):1291-302.

PMID 9883723

Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines.

Chappuis-Flament S, Pasini A, De Vita G, Segouffin-Cariou C, Fusco A, Attie T, Lenoir GM, Santoro M, Billaud M.

Oncogene. 1998 Dec 3;17(22):2851-61.

PMID 9879991

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma.

Chiefari E, Russo D, Giuffrida D, Zampa GA, Meringolo D, Arturi F, Chiodini I, Bianchi D, Attard M, Trischitta V, Bruno R, Giannasio P, Pontecorvi A, Filetti S.

J Endocrinol Invest. 1998 Jun;21(6):358-64.

PMID 9699127

Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience.

Dralle H, Gimm O, Simon D, Frank-Raue K, Görtz G, Niederle B, Wahl RA, Koch B, Walgenbach S, Hampel R, Ritter MM, Spelsberg F, Heiss A, Hinze R, Hoppner W.

World J Surg. 1998 Jul;22(7):744-50; discussion 750-1.

PMID 9606292

Persephin, a novel neurotrophic factor related to GDNF and neurturin.

Milbrandt J, de Sauvage FJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG, Lampe PA, Heuckeroth RO, Kotzbauer PT, Simburger KS, Golden JP, Davies JA, Vejsada R, Kato AC, Hynes M, Sherman D, Nishimura M, Wang LC, Vandlen R, Moffat B, Klein RD, Poulsen K, Gray C, Garces A, Johnson EM Jr, et al.

Neuron. 1998 Feb;20(2):245-53.

PMID 9491986

Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma.

Shirahama S, Ogura K, Takami H, Ito K, Tohsen T, Miyauchi A, Nakamura Y.

J Hum Genet. 1998;43(2):101-6.

PMID 9621513

Oncological implications of RET gene mutations in Hirschsprung's disease.

Sijmons RH, Hofstra RM, Wijburg FA, Links TP, Zwierstra RP, Vermey A, Aronson DC, Tan-Sindhunata G, Brouwers-Smalbraak GJ, Maas SM, Buys CH.

Gut. 1998 Oct;43(4):542-7.

PMID 9824583

A rapid method for DNA extraction from fine-needle aspiration biopsies of thyroid tumors, and subsequent RET mutation analysis.

Zedenius J, Dwight T, Robinson BG, Delbridge L, Backdahl M, Wallin G, Larsson C, Weber G.

Cancer Detect Prev. 1998;22(6):544-8.

PMID 9824378

Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?

Takahashi M, Iwashita T, Santoro M, Lyonnet S, Lenoir GM, Billaud M.

Hum Mutat. 1999;13(4):331-6.

PMID 10220148

Absence of somatic RET gene mutation in sporadic parathyroid tumors and hyperplasia secondary to uremia, and absence of somatic Men1 gene mutation in MEN2A-associated hyperplasia.

Uchino S, Noguchi S, Nagatomo M, Sato M, Yamashita H, Yamashita H, Watanabe S, Murakami T, Toda M, Wakiya S, Adachi M.

Biomed Pharmacother. 2000 Jun;54 Suppl 1:100s-103s.

PMID 10915003

Expression and alternative splicing of c-ret RNA in papillary thyroid carcinomas.

Fluge O, Haugen DR, Akslen LA, Marstad A, Santoro M, Fusco A, Varhaug JE, Lillehaug JR.

Oncogene. 2001 Feb 15;20(7):885-92.

PMID 11314023

Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.

Niccoli-Sire P, Murat A, Rohmer V, Franc S, Chabrier G, Baldet L, Maes B, Savagner F, Giraud S, Bezieau S, Kottler ML, Morange S, Conte-Devolx B; French Calcitonin Tumors Group (GETC).

J Clin Endocrinol Metab. 2001 Aug;86(8):3746-53.

PMID 11502806

Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

Schilling T, Burck J, Sinn HP, Clemens A, Otto HF, Hoppner W, Herfarth C, Ziegler R, Schwab M, Raue F.

Int J Cancer. 2001 Jan 20;95(1):62-6.

PMID 11241313

Malignant progression from C-cell hyperplasia to medullary thyroid carcinoma in 167 carriers of RET germline mutations.

Machens A, Holzhausen HJ, Thanh PN, Dralle H.

Surgery. 2003 Sep;134(3):425-31.

PMID 14555929

Early malignant progression of hereditary medullary thyroid cancer.

Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F, Conte-Devolx B, Dralle H; European Multiple Endocrine Neoplasia (EUROMEN) Study Group.

N Engl J Med. 2003 Oct 16;349(16):1517-25.

PMID 14561794

Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease.

Arighi E, Popsueva A, Degl'Innocenti D, Borrello MG, Carniti C, Perala NM, Pierotti MA, Sariola H.

Mol Endocrinol. 2004 Apr;18(4):1004-17.

PMID 14715928

Identification of a novel point mutation in the RET gene (Ala883Thr), which is associated with medullary thyroid carcinoma phenotype only in homozygous condition.

Elisei R, Cosci B, Romei C, Agate L, Piampiani P, Miccoli P, Berti P, Basolo F, Ugolini C, Ciampi R, Nikiforov Y, Pinchera A.

J Clin Endocrinol Metab. 2004 Nov;89(11):5823-7.

PMID 15531548

A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma.

Jimenez C, Dang GT, Schultz PN, El-Naggar A, Shapiro S, Barnes EA, Evans DB, Vassilopoulou-Sellin R, Gagel RF, Cote GJ, Hoff AO.

J Clin Endocrinol Metab. 2004 Jul;89(7):3521-6.

PMID 15240641

Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A.

Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA Jr.

N Engl J Med. 2005 Sep 15;353(11):1105-13.

PMID 16162881

Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2.

Mise N, Drosten M, Racek T, Tannapfel A, Putzer BM.

Oncogene. 2006 Oct 26;25(50):6637-47.

PMID 16715139

RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center.

Elisei R, Romei C, Cosci B, Agate L, Bottici V, Molinaro E, Sculli M, Miccoli P, Basolo F, Grasso L, Pacini F, Pinchera A.

J Clin Endocrinol Metab. 2007 Dec;92(12):4725-9.

PMID 17895320

Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma.

Machens A, Dralle H.

World J Surg. 2007 May;31(5):957-68.

PMID 17453286

Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study.

Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, Agate L, Vivaldi A, Faviana P, Basolo F, Miccoli P, Berti P, Pacini F, Pinchera A.

J Clin Endocrinol Metab. 2008 Mar;93(3):682-7.

PMID 18073307

Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791.

Frank-Raue K, Machens A, Scheuba C, Niederle B, Dralle H, Raue F; the German MEN2. Study Group.

Clin Endocrinol (Oxf). 2008 Feb 1. Epub ahead of print.

PMID 18248648

New therapeutic approaches to treat medullary thyroid carcinoma.

Schlumberger M, Carlomagno F, Baudin E, Bidart JM, Santoro M.

Nat Clin Pract Endocrinol Metab. 2008 Jan;4(1):22-32.

PMID 18084343

Written	2008-04	Rossella Elisei, Cristina Romei, Barbara Cosci, Eleonora Molinaro, Laura Agate, Valeria Bottici, Aldo Pinchera
		of Endocrinology, Metabolism University of Pisa, Pisa, Italy

Citation

This paper should be referenced as such :

Elisei, R ; Romei, C ; Cosci, B ; Molinaro, E ; Agate, L ; Bottici, V ; Pinchera, A

RET point mutations in Thyroid Carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2009;13(4):325-332.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Deep/RETPointMutID20066.htm