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El carcinoma medular de tiroides (CMT) puede presentarse en forma esporádica o familiar, en cuyo caso se integra en la neoplasia endocrina múltiple tipo 2 (NEM 2). La NEM 2 se origina como consecuencia de mutaciones germinales en el gen RET. Este gen incluye 21 exones y codifica el receptor RET, un receptor de membrana citoplasmática con actividad tirosinacinasa. La peculiaridad de esta alteración reside en la posibilidad de establecer una relación genotipo-fenotipo. Las distintas mutaciones en los codones del gen RET dan lugar a diversos cuadros clínicos, etiquetados clásicamente como NEM 2A, NEM 2B y CMTF (CMT familiar). En los últimos años se ha añadido una nueva clasificación en función de la agresividad del comportamiento tumoral, en la que se distinguen 3 niveles de riesgo. En la presente revisión exponemos las características fisiológicas y patológicas del gen RET, la relación genotipo-fenotipo tanto clásica como por grados de agresividad, los elementos posiblemente modificadores en esa relación (polimorfismos de un único nucleótido), la actitud a adoptar ante el CMT y el tratamiento recomendado según las características genéticas.
Palabras clave:
Carcinoma medular de tiroides
Neoplasia endocrina múltiple tipo 2 (NEM 2) Gen RET
Relación genotipo-fenotipo
Medullary thyroid carcinoma (MTC) can be sporadic or hereditary. The hereditary form of MTC is classified as multiple endocrine neoplasia type 2 (MEN 2). MEN 2 syndromes are caused by germinal mutations in the RET proto-oncogene. The RET gene includes 21 exons and encodes a plasma membrane-bound tyrosine kinase enzyme, the RET receptor. The peculiarity of this disease lies in the possibility of establishing genotype-phenotype correlations.
Distinct RET codon mutations give rise to the different MEN 2 syndromes, traditionally classified as MEN 2A, MEN 2B and familial MTC. In the last few years, a new classification has been suggested, based on biologic tumoral aggressiveness, in which RET mutations are stratified into three levels of risk.
In this review, we explain the physiological and pathological features of the RET gene, genotype-phenotype correlations (both traditional and the new risk classification), the elements that may modify this relationship (such as single nucleotide polymorphisms), suggested clinical decision-making in MTC and genetically-based treatment.
Key words:
Medullary thyroid carcinoma
MEN 2A (multiple endocrine neoplasia type 2)
RET gene
Genotype-phenotype correlation
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Bibliografía
[1.]
S. Leboulleux, E. Baudin, J.P. Travagli, M. Schlumberger.
Medullary thyroid carcinoma.
Clin Endocrinol (Oxf), 61 (2004), pp. 299-310
[2.]
F. Weber, C. Eng.
Germline variants within RET: clinical utility or scientific playtoy? [editorial].
J Clin Endocrinol Metab, 90 (2005), pp. 6334-6336
[3.]
J.B. Hazard, W.A. Hawk, G Crile Jr.
Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity.
J Clin Endocrinol Metab, 19 (1959), pp. 152-161
[4.]
M.A. Kouvaraki, S.E. Shapiro, N.D. Perrier, G.J. Cote, R.F. Gagel, A.O. Hoff, et al.
RET proto-oncogene: A review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors.
Thyroid, 15 (2005), pp. 531-544
[5.]
M.A. Block, C.E. Jackson, K.A. Greenawald, J.B. Yott, A.H. Tashjian Jr.
Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma.
Arch Surg, 115 (1980), pp. 142-148
[6.]
T. Tsuzuki, M. Takahashi, N. Asai, T. Iwashita, M. Matsuyama, J. Asai.
Spatial and temporal expression of the RET protooncogen product in embryonic, infant and adult rat tissues.
Oncogene, 10 (1995), pp. 191-198
[7.]
A. Capes-Davis, B.G. Robinson.
Return of the native: deducing the normal function of the RET proto-oncogen.
Curr Opin Endocrinol Diabetes, 6 (1999), pp. 61-66
[8.]
S. Dvorakova, E. Vaclavikova, V. Sykorova, J. Duskova, P. Vlcek, A. Ryska, et al.
New multiple somatic mutations in the RET proto-oncogene associated with a sporadic medullary carcinoma.
Thyroid, 16 (2006), pp. 311-316
[9.]
J. Zedenius, C. Larsson, U. Bergholm, J. Bovee, A. Svensson, B. Hallengren, et al.
Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas.
J Clin Endocrinol Metab, 80 (1995), pp. 3088-3090
[10.]
O. Gimm, D.S. Neuberg, D.J. Marsh, P.L.M. Dahia, C. Hoang-Vu, F. Raue, et al.
Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.
Oncogene, 18 (1999), pp. 1369-1373
[11.]
A. Ruiz, G. Antinolo, R.M. Fernández, C. Eng, I. Marcos, S. Borrego.
Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population.
Clin Endocrinol (Oxf), 55 (2001), pp. 399-402
[12.]
R. Elisei, B. Cosci, C. Romei, V. Bottici, M. Sculli, R. Lari, et al.
RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population.
J Clin Endocrinol Metab, 89 (2004), pp. 3579-3584
[13.]
S.M. Baumgartner-Parzer, R. Lang, L. Wagner, G. Heinze, B. Niederle, K. Kaserer, et al.
Polymorphisms in exon 13 and intron 14 of the RET protooncogene: Genetic modifiers of medullary thyroid carcinoma?.
J Clin Endocrinol Metab, 90 (2005), pp. 6232-6236
[14.]
R.M. Fernández, A. Pecina, G. Antinolo, E. Navarro, S. Borrego.
Analysis of the RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma.
Thyroid, 16 (2006), pp. 411-417
[15.]
A. Cebrian, F. Lesueur, S. Martin, J. Leyland, S. Ahmed, C. Luccarini, et al.
Polymorphisms in the initiators of RET (Rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma.
J Clin Endocrinol Metab, 90 (2005), pp. 6268-6274
[16.]
S. Borrego, R.M. Fernández, H. Dziema, M.A. Japon, I. Marcos, C. Eng, et al.
Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.
Thyroid, 12 (2002), pp. 1017-1022
[17.]
M.L. Brandi, R.F. Gagel, A. Angeli, J.P. Bilezikian, P. Beck-Peccoz, C. Bordi, et al.
Guidelines for diagnosis and therapy of MEN type 1 and type 2.
J Clin Endocrinol Metab, 86 (2001), pp. 5658-5671
[18.]
C. Eng, D. Clayton, I. Schuffenecker, G. Lenoir, G. Cote, R.F. Gagel, et al.
The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET Mutation Consortium Analysis.
JAMA, 276 (1996), pp. 1575-1579
[19.]
L.M. Mulligan, J.B. Kwok, C.S. Healey, M.J. Elsdon, C. Eng, E. Gardner, et al.
Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2.
Nature, 363 (1993), pp. 458-460
[20.]
F. Raue, K. Frank-Raue, A. Grauer.
Multiple endocrine neoplasia type 2. Clinical features and sreening.
Endocrinol Metab Clin North Am, 23 (1994), pp. 137-156
[21.]
N. Wohllk, G.J. Cote, D.B. Evans, H. Goepfert, N.G. Ordonez, R.F. Gagel.
Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia type 2.
Endocrinol Metab Clin North Am, 25 (1996), pp. 1-25
[22.]
M. Santoro, F. Carlomagno, A. Romano, D.P. Bottaro, N.A. Dathan, M. Grieco, et al.
Activation of RET as a dominant transforming gene by germline mutations of MEN 2A and MEN 2B.
Science, 267 (1995), pp. 381-383
[23.]
N. Mise, M. Drosten, T. Racek, A. Tannapfel, B.M. Putzer.
Evaluation of potencial mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2.
Oncogene, 25 (2006), pp. 6637-6647
[24.]
H.J. Karga, M.K. Karayianni, D.A. Linos, S.C. Tseleni, K.D. Karaiskos, P.D. Papapetrou.
Germ line mutation analysis in families with multiple endocrine neoplasia type 2 A or familial medullary thyroid carcinoma.
Eur J Endocrinol, 139 (1998), pp. 410-415
[25.]
J. Russel, D. Lettieri, L.M. Sherwood.
Suppression by 1,25 (OH)2D3 of transcription of the bovine parathyroid hormone gen.
Endocrinology, 117 (1995), pp. 2114-2116
[26.]
L. Forga, X. Matías-Guiu, M.C. De Miguel, R.M. Rodríguez-Erdozain, M.J. Goñi.
Estudio genético del MEN 2A en Navarra.
Relación genotipo-fenotipo. Endocrinología, 46 (1999), pp. 164-167
[27.]
S. Dvorakova, E. Vaclavikova, A. Ryska, J. Cap, P. Vlcek, J. Duskova, et al.
Double germline mutations in the RET proto-oncogen in MEN 2 A and MEN 2 B kindreds.
Exp Clin Endocrinol Diabetes, 114 (2006), pp. 192-196
[28.]
S. Dvorakova, E. Vaclavikova, J. Duskova, P. Vlcek, B. Bendlova.
Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg.
J Endocrinol Invest, 28 (2005), pp. 905-909
[29.]
L. D’Aloiso, F. Carlomagno, M. Bisceglia, S. Anaganti, E. Ferretti, A. Verrienti, et al.
In vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma.
J Clin Endocrinol Metab, 91 (2006), pp. 754-759
[30.]
O. Chabre, F. Labat, N. Pinel, F. Berthod, V. Tarel, I. Bachelot.
Cutaneous lesion associated with multiple endocrine neoplasia type 2A: Lichen amyloidosis or nostalgia parethetica?.
Henry Ford Hosp Med J, 40 (1992), pp. 245-248
[32.]
U. Verga, L. Fugazzola, S. Cambiaghi, C. Pritelli, E. Alessi, D. Cortelazzi, et al.
Frequent association between MEN 2A and cutaneous lichen amyloidosis.
Clin Endocrinol (Oxf), 59 (2003), pp. 156-161
[33.]
J.P. Ferrer, I. Halperin, J.I. Conget, M. Alsina, M.J. Martínez-Osaba, J. Palou, et al.
Primary localized cutaneous amyloidosis and familial medullary carcinoma.
Clin Endocrinol (Oxf), (1991), pp. 34435-34439
[34.]
S. Borrego, C. Eng, B. Sánchez, M.E. Sáez, E. Navarro, G. Antiñolo.
Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2 A and Hirschsprung disease.
J Clin Endocrinol Metab, 83 (1998), pp. 3361-3364
[35.]
R. Elisei, B. Cosci, C. Romei, L. Agate, P. Piampiani, P. Miccoli, et al.
Identification of a novel point mutation in the RET gene (Ala883Thr), which is associated with medullary thyroid carcinoma phenotype only in homozygous condition.
J Clin Endocrinol Metab, 89 (2004), pp. 5823-5827
[36.]
W.B. Kinlaw, S.M. Scout, R.A. Maue, V.A. Memoli, R.D. Harris, G.H. Daniels, et al.
Multiple endocrine neoplasia 2A due to a unique C609S RET mutation presents with pheochromocytoma and reduced penetrance of medullary thyroid carcinoma.
Clin Endocrinol (Oxf), 63 (2005), pp. 676-682
[37.]
M. Robledo, L. Gil, M. Pollán, A. Cebrián, S Ruiz, M. Azanedo, et al.
Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2 A.
Cancer Res, 63 (2003), pp. 1814-1817
[38.]
F. Lesueur, A. Cebrián, M. Robledo, P. Niccoli-Sire, K.A. Svensson, S. Pinson, et al.
Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A.
Cancer Res, 66 (2006), pp. 1177-1180
[39.]
C. Eng, M.L. Mulligan, D.P. Smith, C.S. Healey, A. Frilling, F. Raue, et al.
Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.
Clin Endocrinol (Oxf), 43 (1995), pp. 123-127
[40.]
G. Opocher, F. Schiavi, P. Conton, C. Scaroni, F. Mantero.
Clinical and genetic aspects of phaeochromocytoma.
Horm Res, 59 (2003), pp. 56-61
[41.]
Y. Alderazi, M.W. Yeh, B.G. Robinson, D.E. Benn, M.S. Sywak, D.L. Learoyd, et al.
Phaeochromocytoma: current concepts.
Med J Aust, 183 (2005), pp. 201-204
[42.]
C. Fuentes, E. Menéndez, J. Pineda, J.P. Martínez de Esteban, E. Anda, M.J. Goñi, et al.
The malignant potential of a succinate dehydrogenase subunit B germline mutation.
J Endocrinol Invest, 29 (2006), pp. 350-352
[43.]
A. Calender, S. Dupasquier, M. Cordier, C.X. Zhang, Groupe d’etude des tumeurs endocrines.
Genetics of endocrine tumours.
Ann Pathol, 25 (2005), pp. 463-486
[44.]
M.A. Skinner, J.A. Moley, W.G. Dilley, K. Owzar, M.K. De Benedetti, S.A. Wells.
Prophylactic thyroidectomy in multiple endocrine neoplasia type 2 A.
N Engl J Med, 353 (2005), pp. 1105-1113
[45.]
T.W. Yen, S.E. Shapiro, R.F. Gagel, S.I. Sherman, J.E. Lee, D.B. Evans.
Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients.
Surgery, 134 (2003), pp. 890-899
[46.]
C. Piolat, J.F. Dyon, N. Sturm, S. Pinson, M. Bost, P.S. Jouk, et al.
Very early prophylactic thyroid surgery for infants with a mutation of the RET proto-oncogene at codon 634: evaluation of the implementation of internacional guidelines for MEN type 2 in a simple centre.
Clin Endocrinol (Oxf), 65 (2006), pp. 118-124
[47.]
P. Kaldrymides, N. Mytakidis, T. Anagnostopoulos, M. Vassiliou, A. Tertipi, M. Zahariou, et al.
A rare RET exon mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening.
Clin Endocrinol (Oxf), 64 (2006), pp. 561-566
[48.]
T. Dabir, S.J. Hunter, C.F.J. Russell, D. McCall, P.J. Morrison.
The RET mutation E768D confers a late-onset familial medullary thyroid carcinoma – only phenotype with incomplete penetrance: Implications for screening and management of carrier status.
Familial Cancer, 5 (2006), pp. 201-204
[49.]
D.L. Learoyd, J. Gosnell, M.S. Lestón, T.J. Saurine, A.L. Richardson, L.W. Delbridge, et al.
Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2 A kindreds with RET codon 804 mutations.
Clin Endocrinol (Oxf), 63 (2005), pp. 636-641
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