FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 349:1517-1525 October 16, 2003 Number 16 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Cote, G. J. Letters Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery.

Methods In this European multicenter study conducted from July 1993 to February 2001, we enrolled patients who had a RET point mutation in the germ line, were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Exclusion criteria were medullary thyroid carcinomas of more than 10 mm in greatest dimension and distant metastasis.

Results Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with the codon 634 genotype. No lymph-node metastases were noted in patients younger than 14 years of age. The age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations. The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of the individual RET mutation.

Conclusions These data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.

Source Information

From the Klinik für Allgemein-, Viszeral-, und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany (A.M., H.D.); the Centre Hospitalier Régional et Universitaire de Marseille, Service d'Endocrinologie et Maladies Métaboliques, Marseilles, France (P.N.-S., B.C.-D.); the Abteilung Biometrie und Medizinische Dokumentation, Universität Ulm, Ulm, Germany (J.H.); the Endokrinologische Gemeinschaftspraxis, Heidelberg, Germany (K.F.-R., F.R.); the Department of Surgery, University Hospital Utrecht, Utrecht, the Netherlands (T.J.V.); the Klinik für Allgemeine und Unfallchirurgie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (H.-D.R.); the Chirurgische Klinik, Bürgerhospital Frankfurt am Main, Frankfurt am Main, Germany (R.A.W.); and the Chirurgische Klinik und Poliklinik für Abdominal-, Transplantations-, und Gefäßchirurgie, Universität Leipzig, Leipzig, Germany (P.L.).

Address reprint requests to Dr. Machens at the Klinik für Allgemein-, Viszeral-, und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany, or at gensurg{at}medzin.uni-halle.de.

Full Text of this Article

Related Letters:

Early Malignant Progression of Hereditary Medullary Thyroid Cancer
Machens A.
Extract | Full Text | PDF  
N Engl J Med 2004; 350:943, Feb 26, 2004. Correspondence

Childhood Progression of Hereditary Medullary Thyroid Cancer
Chabre O., Piolat C., Dyon J.-F., Machens A., Hoegel J., Dralle H.
Extract | Full Text | PDF  
N Engl J Med 2007; 356:1583-1585, Apr 12, 2007. Correspondence

This article has been cited by other articles:

• Zenaty, D, Aigrain, Y, Peuchmaur, M, Philippe-Chomette, P, Baumann, C, Cornelis, F, Hugot, J P, Chevenne, D, Barbu, V, Guillausseau, P J, Schlumberger, M, Carel, J C, Travagli, J P, Leger, J (2009). Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B. Eur J Endocrinol 160: 807-813 [Abstract] [Full Text]  
• Sakorafas, G. H, Friess, H., Peros, G. (2008). The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15: 871-884 [Abstract] [Full Text]  
• Milos, I. N, Frank-Raue, K., Wohllk, N., Maia, A. L., Pusiol, E., Patocs, A., Robledo, M., Biarnes, J., Barontini, M., Links, T. P, de Groot, J. W., Dvorakova, S., Peczkowska, M., Rybicki, L. A, Sullivan, M., Raue, F., Zosin, I., Eng, C., Neumann, H. P H (2008). Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer 15: 1035-1041 [Abstract] [Full Text]  
• Peppa, M., Boutati, E., Kamakari, S., Pikounis, V., Peros, G., Panayiotides, I. G, Economopoulos, T., Raptis, S. A, Hadjidakis, D. (2008). Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. Eur J Endocrinol 159: 767-771 [Abstract] [Full Text]  
• Wuttke, M., Papewalis, C., Meyer, Y., Kessler, C., Jacobs, B., Willenberg, H. S., Schinner, S., Kouatchoua, C., Baehring, T., Scherbaum, W. A., Schott, M. (2008). Amino Acid-Modified Calcitonin Immunization Induces Tumor Epitope-Specific Immunity in a Transgenic Mouse Model for Medullary Thyroid Carcinoma. Endocrinology 149: 5627-5634 [Abstract] [Full Text]  
• Papewalis, C., Wuttke, M., Seissler, J., Meyer, Y., Kessler, C., Jacobs, B., Ullrich, E., Willenberg, H. S., Schinner, S., Baehring, T., Scherbaum, W. A., Schott, M. (2008). Dendritic Cell Vaccination with Xenogenic Polypeptide Hormone Induces Tumor Rejection in Neuroendocrine Cancer. Clin. Cancer Res. 14: 4298-4305 [Abstract] [Full Text]  
• Colombo-Benkmann, M., Li, Z., Riemann, B., Hengst, K., Herbst, H., Keuser, R., Gross, U., Rondot, S., Raue, F., Senninger, N., Putzer, B. M, Frank-Raue, K. (2008). Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma.. Eur J Endocrinol 158: 811-816 [Abstract] [Full Text]  
• Sippel, R. S., Kunnimalaiyaan, M., Chen, H. (2008). Current Management of Medullary Thyroid Cancer. The Oncologist 13: 539-547 [Abstract] [Full Text]  
• Beckers, A., Daly, A. F (2007). The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 157: 371-382 [Abstract] [Full Text]  
• Frank-Raue, K., Fabel, M., Delorme, S., Haberkorn, U., Raue, F. (2007). Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol 157: 215-220 [Abstract] [Full Text]  
• Chabre, O., Piolat, C., Dyon, J.-F., Machens, A., Hoegel, J., Dralle, H. (2007). Childhood Progression of Hereditary Medullary Thyroid Cancer. NEJM 356: 1583-1585 [Full Text]  
• Frank-Raue, K, Buhr, H, Dralle, H, Klar, E, Senninger, N, Weber, T, Rondot, S, Hoppner, W, Raue, F (2006). Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype.. Eur J Endocrinol 155: 229-236 [Abstract] [Full Text]  
• de Groot, J. W. B., Links, T. P., Plukker, J. T. M., Lips, C. J. M., Hofstra, R. M. W. (2006). RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors. Endocr. Rev. 27: 535-560 [Abstract] [Full Text]  
• Carlomagno, F., Anaganti, S., Guida, T., Salvatore, G., Troncone, G., Wilhelm, S. M., Santoro, M. (2006). BAY 43-9006 inhibition of oncogenic RET mutants.. JNCI J Natl Cancer Inst 98: 326-334 [Abstract] [Full Text]  
• Skinner, M. A., Moley, J. A., Dilley, W. G., Owzar, K., DeBenedetti, M. K., Wells, S. A. Jr. (2005). Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia Type 2A. NEJM 353: 1105-1113 [Abstract] [Full Text]  
• Moore, F. D., Dluhy, R. G. (2005). Prophylactic Thyroidectomy in MEN-2A -- A Stitch in Time?. NEJM 353: 1162-1164 [Full Text]  
• Jackson, M. B., Guttenberg, M., Hedrick, H., Moshang, T. Jr (2005). Multiple Endocrine Neoplasia Type 2A in a Kindred With C634Y Mutation. Pediatrics 116: e468-e471 [Abstract] [Full Text]  
• Marx, S. J., Simonds, W. F. (2005). Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes. Endocr. Rev. 26: 615-661 [Abstract] [Full Text]  
• Frank-Raue, K., Rondot, S., Hoeppner, W., Goretzki, P., Raue, F., Meng, W. (2005). Coincidence of Multiple Endocrine Neoplasia Types 1 and 2: Mutations in the RET Protooncogene and MEN1 Tumor Suppressor Gene in a Family Presenting with Recurrent Primary Hyperparathyroidism. J. Clin. Endocrinol. Metab. 90: 4063-4067 [Abstract] [Full Text]  
• Machens, A., Brauckhoff, M., Holzhausen, H.-J., Thanh, P. N., Lehnert, H., Dralle, H. (2005). Codon-Specific Development of Pheochromocytoma in Multiple Endocrine Neoplasia Type 2. J. Clin. Endocrinol. Metab. 90: 3999-4003 [Abstract] [Full Text]  
• Cascon, A., Cebrian, A., Pollan, M., Ruiz-Llorente, S., Montero-Conde, C., Leton, R., Gutierrez, R., Lesueur, F., Milne, R. L., Gonzalez-Albarran, O., Lucas-Morante, T., Benitez, J., Ponder, B. A. J., Robledo, M. (2005). Succinate Dehydrogenase D Variants Do Not Constitute a Risk Factor for Developing C Cell Hyperplasia or Sporadic Medullary Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 90: 2127-2130 [Abstract] [Full Text]  
• Santoro, M., Melillo, R. M., Carlomagno, F., Vecchio, G., Fusco, A. (2004). Minireview: RET: Normal and Abnormal Functions. Endocrinology 145: 5448-5451 [Abstract] [Full Text]  
• Jindrichova, S, Vcelak, J, Vlcek, P, Neradilova, M, Nemec, J, Bendlova, B (2004). Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol 183: 257-265 [Abstract] [Full Text]  
• Elisei, R., Cosci, B., Romei, C., Agate, L., Piampiani, P., Miccoli, P., Berti, P., Basolo, F., Ugolini, C., Ciampi, R., Nikiforov, Y., Pinchera, A. (2004). 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: 5823-5827 [Abstract] [Full Text]  
• Jimenez, C., Habra, M. A., Huang, S.-C. E., El-Naggar, A., Shapiro, S. E., Evans, D. B., Cote, G., Gagel, R. F. (2004). Pheochromocytoma and Medullary Thyroid Carcinoma: A New Genotype-Phenotype Correlation of the RET Protooncogene 891 Germline Mutation. J. Clin. Endocrinol. Metab. 89: 4142-4145 [Abstract] [Full Text]  
• Melillo, R. M., Cirafici, A. M., De Falco, V., Bellantoni, M., Chiappetta, G., Fusco, A., Carlomagno, F., Picascia, A., Tramontano, D., Tallini, G., Santoro, M. (2004). The Oncogenic Activity of RET Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma. Am. J. Pathol. 165: 511-521 [Abstract] [Full Text]  
• Jimenez, C., Dang, G. T., Schultz, P. N., El-Naggar, A., Shapiro, S., Barnes, E. A., Evans, D. B., Vassilopoulou-Sellin, R., Gagel, R. F., Cote, G. J., Hoff, A. O. (2004). A Novel Point Mutation of the RET Protooncogene Involving the Second Intracellular Tyrosine Kinase Domain in a Family with Medullary Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 89: 3521-3526 [Abstract] [Full Text]  
• Kaltsas, G. A., Besser, G. M., Grossman, A. B. (2004). The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors. Endocr. Rev. 25: 458-511 [Abstract] [Full Text]  
• Jain, S., Watson, M. A., DeBenedetti, M. K., Hiraki, Y., Moley, J. F., Milbrandt, J. (2004). Expression Profiles Provide Insights into Early Malignant Potential and Skeletal Abnormalities in Multiple Endocrine Neoplasia Type 2B Syndrome Tumors. Cancer Res. 64: 3907-3913 [Abstract] [Full Text]  
• Machens, A. (2004). Early Malignant Progression of Hereditary Medullary Thyroid Cancer. NEJM 350: 943-943 [Full Text]  
• Cote, G. J., Gagel, R. F. (2003). Lessons Learned from the Management of a Rare Genetic Cancer. NEJM 349: 1566-1568 [Full Text]