J Korean Endocr Soc.  2009 Dec;24(4):293-297. 10.3803/jkes.2009.24.4.293.

A Case of Sporadic Medullary Thyroid Cancer with RET G691S Polymorphism

  • 1Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea.


Sporadic medullary thyroid carcinoma (MTC) is the most common form of MTC and somatic RET proto-oncogene mutations account for approximately 25% of the patients with sporadic MTC. However, other pathogeneses of sporadic MTC are still unclear. Not only RET mutation, but also polymorphisms of RET may have an association with sporadic MTC. We herein describe the association of MTC and RET proto-oncogene polymorphism. A 51-year-old man was diagnosed with MTC, which was incidentally found on a thyroid sonogram. The patient underwent total thyroidectomy and genetic mutational analysis of the RET gene. Genetic testing detected a polymorphism in codon 691 (G691S) on exon 11 of the RET proto-oncogene. His son and daughter had the same polymorphism. We report on this case along with a review of the related literature on RET gene polymorphism of sporadic MTC.


polymorphism; RET proto-oncogene; sporadic medullary thyroid carcinoma

MeSH Terms

Genetic Testing
Middle Aged
Nuclear Family
Thyroid Gland
Thyroid Neoplasms


  • Fig. 1 Ultrasonogram shows 1.7 × 1.3 cm-sized dense calcified nodular lesion on left thyroid gland (A) and another 0.9 cm nodule found on lateral part of neck (B).

  • Fig. 2 Neck computed tomography shows a dense calcified nodule in thyroid (A) and enlarged lymph nodes (B).

  • Fig. 3 Immunohistochemical stain of the medullary thyroid carcinoma (Calcitonin stain ×400). The tumor cells are stained with calcitonin.

  • Fig. 4 RET proto-oncogene testing detected a polymorphism in codon 691 (G691S) on exon 11 of the RET proto-oncogene.

  • Fig. 5 The patient's pedigree shows 3 members with a polymorphism in codon 691 (G691S) of the RET proto-oncogene. The other members were not tested for the polymorphism. Arrow indicates proband.


1. Jimenez C, Hu MI, Gagel RF. Management of medullary thyroid carcinoma. Endocrinol Metab Clin North Am. 2008. 37:481–496.
2. Cardot-Bauters C, Leteurtre E, Leclerc L, Vantyghem MC, Do Cao C, Wemeau JL, d'Herbomez M, Carnaille B, Barbu V, Pinson S, Pigny P. Groupe d'Etude des Tumeurs Endocrines (GTE). Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma? Clin Endocrinol (Oxf). 2008. 69:506–510.
3. Cebrian A, Lesueur F, Martin S, Leyland J, Ahmed S, Luccarini C, Smith PL, Luben R, Whittaker J, Pharoah PD, Dunning AM, Ponder BA. Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005. 90:6268–6274.
4. Elisei R, Cosci B, Romei C, Bottici V, Sculli M, Lari R, Barale R, Pacini F, Pinchera A. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab. 2004. 89:3579–3584.
5. Fugazzola L, Muzza M, Mian C, Cordella D, Barollo S, Alberti L, Cirello V, Dazzi D, Girelli ME, Opocher G, Beck-Peccoz P, Persani L. RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series. Clin Endocrinol (Oxf). 2008. 69:418–425.
6. Robledo M, Gil L, Pollan M, Cebrian A, Ruiz S, Azanedo M, Benitez J, Menarguez J, Rojas JM. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 2003. 63:1814–1817.
7. Fernandez RM, Pecina A, Antinolo G, Navarro E, Borrego S. Analysis of RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma. Thyroid. 2006. 16:411–417.
8. Weinhaeusel A, Scheuba C, Lauss M, Kriegner A, Kaserer K, Vielinger K, Haas OA, Niederle B. The influence of gender, age, and RET polymorphisms on C-cell hyperplasia and medullary thyroid carcinoma. Thyroid. 2008. 18:1269–1276.
9. Wohllk GN, Soto CE, Bravo AM, Becker CP. G691S, L769L and S836S ret proto-oncogene polymorphisms are not associated with higher risk to sporadic medullary thyroid carcinoma in Chilean patients. Rev Med Chil. 2005. 133:397–402.
10. Kim HH, Kim HJ, Chung YJ, Min YK, Lee MS, Lee MK, Kim KW, Ki CS, Kim JW, Chung JH. Analysis of RET proto-oncogene mutation in Korean patients with medullary thyroid carcinomas. J Korean Soc Endocrinol. 2003. 18:360–370.
11. Yun SW, Yoo WS, Hong KH, Kim BH, Kang MH, Choo YK, Park HY, Kim DH, Chung HK, Chang MC, Kwon MS, Kim HJ. A family of multiple endocrine neoplasia type 2A with a C634R mutation and a G691S polymorphism in RET proto-oncogene. J Korean Soc Endocrinol. 2007. 22:453–459.
12. Schilling T, Bürck J, Sinn HP, Clemens A, Otto HF, Höppner W, Herfarth C, Ziegler R, Schwab M, Raue F. Prognostic value of codon 918 (ATG→ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001. 95:62–66.
13. Wohllk N, Cote GJ, Bugalho MM, Ordonez N, Evans DB, Goepfert H, Khorana S, Schultz P, Richards CS, Gagel RF. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 1996. 81:3740–3745.
14. Borrego S, Wright FA, Fernandez RM, Williams N, Lopez-Alonso M, Davuluri R, Antinolo G, Eng C. A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschprung disease and a subset of cases of sporadic medullary thyroid carcinoma. Am J Hum Genet. 2003. 72:88–100.
15. Gursoy A, Erdogan MF, Erdogan G. Significance of the RET proto-oncogene polymorphisms in Turkish sporadic medullary thyroid carcinoma patients. J Endocrinol Invest. 2006. 29:858–862.
16. Ruiz A, Antinolo G, Fernandez RM, Eng C, Marcos I, Borrego S. 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). 2001. 55:399–402.
17. Sawai H, Okada Y, Kazanjian K, Kim J, Hasan S, Hines OJ, Reber HA, Hoon DS, Eibl G. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005. 65:11536–11544.
18. Uchino S, Noguchi S, Adachi M, Sato M, Yamashita H, Watanabe S, Murakami T, Toda M, Murakami N, Yamashita H. Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas. Jpn J cancer Res. 1998. 89:411–418.
Full Text Links
  • JKES
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr