Journal of Endocrinological Investigation

, Volume 29, Issue 10, pp 858–862 | Cite as

Significance of the RET proto-oncogene polymorphisms in Turkish sporadic medullary thyroid carcinoma patients

Original Articles
First Online:
Accepted:

Abstract

Several single nucleotide polymorphisms (SNP) of the RET gene have been identified in medullary thyroid carcinoma (MTC) patients as well as in the general population. However, the relevance of SNP for MTC patients is still controversial, whether these allelic variants play other interacting, predisposing or modifying roles in clinical behavior of MTC. The aim of this work is to elaborate allelic frequencies of the RET proto-oncogene polymorphisms in Turkish sporadic MTC patients and to demonstrate if there is an association between SNP and the clinical disease features, specifically the age at onset of MTC and lymph node involvement at diagnosis. We analyzed the allelic frequencies of SNP of the exon 11, 13, 14 and 15 of the RET proto-oncogene in blood samples from 50 sporadic MTC patients, using the polymerase chain reaction methodology followed by DNA sequencing. The observed allelic frequencies were 24% for G691S polymorphism in exon 11, 29% for L769L polymorphism in exon 13, 5% for S836S polymorphism in exon 14, and 26% for S904S polymorphism in exon 15. These frequencies are similar to those reported in other countries. We did not observe any significant association of all four SNP with the age at onset of MTC. Our results indicate a possible association between the presence of lymph node involvement at the time of diagnosis (extent of disease) and L769L or S836S polymorphism. However, it is not possible to draw definitive conclusions that these two polymorphisms play a significant role in clinical behavior of MTC. Further studies are needed to evaluate the role of this polymorphism in the clinical behavior of MTC.

Key-words

RET proto-oncogene sporadic medullary thyroid carcinoma polymorphisms age of onset lymph node involvement 
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References

  1. 1.
    Raue F, Frank-Raue K, Grauer A. Multiple endocrine neoplasia type 2. Clinical features and screening. Endocrinol Metab Clin North Am 1994, 23: 137–56.PubMedGoogle Scholar
  2. 2.
    Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993, 2: 851–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993, 363: 458–60.PubMedCrossRefGoogle Scholar
  4. 4.
    Eng C, Clayton D, Schuffenecker I, et al. The relation between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplaia type 2: international RET Mutation Consortium analysis. JAMA 1996, 276: 1575–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Edery P, Attie T, Mulligan LM, et al. A novel polymorphism in the coding sequence of the human RET proto-oncogene. Hum Genet 1994, 94: 579–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Bugalho MJ, Cote GJ, Khorana S, Schultz PN, Gagel RF. Identification of a polymorphism in exon 11 of the RET proto-oncogene. Hum Mol Genet 1994, 3: 2263.PubMedCrossRefGoogle Scholar
  7. 7.
    Baumgartner-Parzer SM, Lang R, Wagner L, et al. Polymorphisms in exon 13 and intron 14 of the RET proto-oncogene: Genetic modifiers of medullary thyroid carcinoma? J Clin Endocrinol Metab 2005, 90: 6232–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Cebrian A, Lesueur F, Martin S, et al. Polymorphisms in the initiators of RET signalling pathway and susceptibility to sporadic Medullary Thyroid Carcinoma. J Clin Endocrinol Metab 2005, 90: 6268–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Robledo M, Gil L, Pollan M, et al. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res 2003, 63: 1814–7.PubMedGoogle Scholar
  10. 10.
    Elisei R, Cosci B, Romei C, et al. RET exon 11 (G691 S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab 2005, 89: 3579–84.CrossRefGoogle Scholar
  11. 11.
    Gimm O, Neuberg DS, Marsh DJ, et al. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene 1999, 18: 1369–73.PubMedCrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    Wiench M, Wloch J, Wygoda Z, et al. RET polymorphisms in codons 769 and 836 are not associated with predisposition to medullary thyroid carcinoma. Cancer Detect Prev 2004, 28: 231–6.PubMedCrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    Berard I, Kraimps JL, Savagner F, et al. Germline-sequence variants S836S and L769L in the RE arranged during Transfection (RET) proto-oncogene are not associated with predisposition to sporadic medullary carcinoma in the French population. Clin Genet 2004, 65: 150–2.PubMedCrossRefGoogle Scholar
  16. 16.
    Vineis P. Individual susceptibility to carcinogens. Oncogene 2004, 23: 6477–83.PubMedCrossRefGoogle Scholar
  17. 17.
    Costa P, Domingues R, Sobrinho LG, Joao Bugalho M. RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population. Endocrine 2005, 27: 239–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Erdogan MF, Gursoy A, Ozgen G, et al. Ret proto-oncogene mutations in apparently sporadic Turkish medullary thyroid carcinoma patients: Turkmen study. J Endocrinol Invest 2005, 28: 806–9.PubMedGoogle Scholar
  19. 19.
    Magalhaes PK, de Castro M, Elias LL, Soares EG, Maciel LM. Polymorphisms in the RET proto-oncogene and the phenotypic presentation of familial medullary thyroid carcinoma. Thyroid 2004, 14: 848–52.PubMedCrossRefGoogle Scholar
  20. 20.
    Santoro M, Melillo RM, Carlomagno F, Fusco A, Vecchio G. Molecular mechanisms of RET activation in human cancer. Ann N Y Acad Sci 2002, 963: 116–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Kurokawa K, Kawai K, Hashimoto M, Ito Y, Takahashi M. Cell signalling and gene expression mediated by RET tyrosine kinase. J Intern Med 2003, 253: 627–33.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2006

Authors and Affiliations

  1. 1.Department of Endocrinology and Metabolic DiseasesAnkara University School of MedicineAnkaraTurkey

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