Advertisement

Hormones

, Volume 15, Issue 1, pp 65–72 | Cite as

Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A

  • Maryam Nasiri Aghdam
  • Mohammad Reza Abbaszadegan
  • Alireza Tafazoli
  • Mohammad Aslzare
  • Zohreh Mosavi
Research paper

Abstract

PURPOSE: Multiple Endocrine Neoplasia type 2A(MEN2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germ line RET (REarranged in Transfection) mutation is required to make the diagnosis and initiate genetic counseling. METHODS: We analyzed blood DNA from three Iranian families with three generations of MEN2A including 20 affected individuals with MTC and four with pheochromocytoma. RET hotspots were amplified in probands and sequenced for mutation detection. RESULT: The causative mutation in all families was found to be the Cys634Tyr missense substitution. The presence of a functional SNP resulting in Gly691Ser was also detected in exon 11 of 15 affected cases. Four patients showed both of these RET variations. CONCLUSION: Our study shows that the Cys634Tyr missense substitution and the Gly691Ser polymorphism are recurrent in Iranian patients, since our families are unrelated. All asymptomatic carriers of the Cys634Tyr high-risk activating mutation were referred for prophylactic thyroidectomy.

Key words

Cys634Tyr mutation Gly691Ser polymorphism Multiple Endocrine Neoplasia type 2A RET proto-oncogene 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H, 1988 Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3: 571–578.PubMedGoogle Scholar
  2. 2.
    Machens A, Lorenz K, Dralle H, 2009 Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med 266: 114–125.CrossRefPubMedGoogle Scholar
  3. 3.
    Airaksinen MS, Saarma M, 2002 The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3: 383–394.CrossRefPubMedGoogle Scholar
  4. 4.
    Imai T, Uchino S, Okamoto T, et al, 2013 High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. Eur J Endocrinol 168: 683–687.CrossRefPubMedGoogle Scholar
  5. 5.
    Wells SA Jr, Asa SL, Dralle H, 2015 Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid 25: 567–610.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Keiser HR, Beaven MA, Doppman J, Wells S Jr., Buja LM, 1973 Sipple’s syndrome: medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Studies in a large family. NIH conference. Ann Intern Med 78: 561–579.CrossRefPubMedGoogle Scholar
  7. 7.
    Pinna G, Orgiana G, Riola A, et al, 2007 RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid 17: 101–104.CrossRefPubMedGoogle Scholar
  8. 8.
    Berndt I, Reuter M, Saller B, et al, 1998 A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 83: 770–774.PubMedGoogle Scholar
  9. 9.
    Machens A, Dralle H, 2008 Familial prevalence and age of RET germline mutations: implications for screening. Clinical endocrinol 69: 81–87.CrossRefGoogle Scholar
  10. 10.
    Machens A, Niccoli-Sire P, Hoegel J, et al, 2003 Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 349: 1517–1525.CrossRefPubMedGoogle Scholar
  11. 11.
    Machens A, Lorenz K, Dralle H, 2009 Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Ann Surg 250: 305–310.CrossRefPubMedGoogle Scholar
  12. 12.
    Martucciello G, Lerone M, Bricco L, et al, 2012 Multiple endocrine neoplasias type 2B and RET proto-oncogene. Ital JPediatr 38: 9.CrossRefGoogle Scholar
  13. 13.
    American Thyroid Association Guidelines Task F, Kloos RT, Eng C, Evans DB, et al, 2009 Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19: 565–612.CrossRefGoogle Scholar
  14. 14.
    Zhou Y, Zhao Y, Cui B, et al, 2007 RET proto-oncogene mutations are restricted to codons 634 and 918 in mainland Chinese families with MEN2A and MEN2B. Clin Endocrinol(Oxf) 67: 570–576.Google Scholar
  15. 15.
    Manie S, Santoro M, Fusco A, Billaud M, 2001 The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 17: 580–589.CrossRefPubMedGoogle Scholar
  16. 16.
    Landsvater RM, de Wit MJ, Zewald RA, et al, 1996 Somatic mutations of the RET proto-oncogene are not required for tumor development in multiple endocrine neoplasia type 2 (MEN 2) gene carriers. Cancer Res 56: 4853–4855.PubMedGoogle Scholar
  17. 17.
    Huang SC, Koch CA, Vortmeyer AO, et al, 2000 Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas. Cancer Res 60: 6223–6226.PubMedGoogle Scholar
  18. 18.
    Koch CA, Huang SC, Moley JF, et al, 2001 Allelic imbalance of the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma. Oncogene 20: 7809–7811.CrossRefPubMedGoogle Scholar
  19. 19.
    Huang SC, Torres-Cruz J, Pack SD, et al, 2003 Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma. J Clin Endocrinol Metab 88: 459–463.CrossRefPubMedGoogle Scholar
  20. 20.
    Mosavi Z, Abdinejad A 1992 Familial Medullary Thyroid Carcinoma. Report of 15 cases in a family members. The Second International Congress on Endocrine Disorders; Tehran-Iran.Google Scholar
  21. 21.
    Brandi ML, Gagel RF, Angeli A, et al, 2001 Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86: 5658–5671.CrossRefPubMedGoogle Scholar
  22. 22.
    Hoff AO, Cote GJ, Gagel RF, 2000 Multiple endocrine neoplasias. Annu Rev Physiol 62: 377–411.CrossRefPubMedGoogle Scholar
  23. 23.
    Niccoli-Sire P, Murat A, Baudin E, et al, 1999 Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinolo 141: 468–474.CrossRefGoogle Scholar
  24. 24.
    Eng C, Smith DP, Mulligan LM, et al, 1994 Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3: 237–241.CrossRefPubMedGoogle Scholar
  25. 25.
    Punales MK, Graf H, Gross JL, Maia AL, 2003 RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab 88: 2644–2649.CrossRefPubMedGoogle Scholar
  26. 26.
    Toledo SP, dos Santos MA, Toledo Rde A, Lourenco DM Jr, 2006 Impact of RET proto-oncogene analysis on the clinical management of multiple endocrine neoplasia type 2. Clinics (Sao paulo) 61: 59–70.CrossRefGoogle Scholar
  27. 27.
    Marx SJ, 2005 Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 5: 367–375.CrossRefPubMedGoogle Scholar
  28. 28.
    Lupianez DG, Kraft K, Heinrich V, et al, 2015 Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161: 1012–1025.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lantieri F, Caroli F, Ceccherini I, Griseri P, 2013 The involvement of the RET variant G691S in medullary thyroid carcinoma enlightened by a meta-analysis study. Int J Cancer 132: 2808–2819.CrossRefPubMedGoogle Scholar
  30. 30.
    Machens A, Frank-Raue K, Lorenz K, Rondot S, Raue F, Dralle H, 2012 Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer. Clin Endocrinol 76: 691–697.CrossRefGoogle Scholar
  31. 31.
    Robledo M, Gil L, Pollán M, et al, 2003 Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res 63: 1814–1817.PubMedGoogle Scholar
  32. 32.
    Borrello MG, Aiello A, Peissel B, et al, 2011 Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. Endocr Relat Cancer 18: 519–527.CrossRefPubMedGoogle Scholar
  33. 33.
    Machens A, Lorenz K, Sekulla C, et al, 2013 Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium. Eur J Endocrinol 168: 307–314.CrossRefPubMedGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2016

Authors and Affiliations

  • Maryam Nasiri Aghdam
    • 1
  • Mohammad Reza Abbaszadegan
    • 2
  • Alireza Tafazoli
    • 1
  • Mohammad Aslzare
    • 3
  • Zohreh Mosavi
    • 3
  1. 1.Medical Genetics Research Center, Department of Medical Genetics, School of MedicineMashhad University of Medical SciencesMashhadIran
  2. 2.Division of Human Genetics, Immunology Research Center, Avicena Research InstituteMashhad University of Medical SciencesMashhadIran
  3. 3.Endocrine Research Center, Imam Reza/Ghaem Hospital, School of MedicineMashhad University of Medical SciencesMashhadIran

Personalised recommendations