769
Views
27
CrossRef citations to date
0
Altmetric
Review Article

Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer

, , &
Pages 217-227 | Received 02 Sep 2014, Accepted 05 Dec 2015, Published online: 27 Jan 2016

References

  • Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 2006;6:292–306
  • Omur O, Baran Y. An update on molecular biology of thyroid cancers. Crit Rev Oncol/Hematol 2014;90:233–52
  • National Cancer Institute at the National Institutes of Health (database on the Internet). Bethesda (MD): National Cancer. Institute at the National Institutes of Health. 2015. Available from: Available from: http://seer.cancer.gov/statfacts/html/thyro.html [last accessed 27 Mar 2015]
  • Phay JE, Shah MH. Targeting RET receptor tyrosine kinase activation in cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 2010;16:5936–41
  • Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Mol Genetics 1993;2:851–6
  • 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
  • Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos, 2012. CA: Cancer J Clin 2012;62:283–98
  • Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 2006;107:2134–42
  • Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 2013;98:E364–9
  • de Groot JW, Plukker JT, Wolffenbuttel BH, et al. Determinants of life expectancy in medullary thyroid cancer: age does not matter. Clin Endocrinol 2006;65:729–36
  • Pellegriti G, Leboulleux S, Baudin E, et al. Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer 2003;88:1537–42
  • Jaquet AJ. Ein fall von metastasierenden amyloidtumoren (lymphosarcoma). Virchow's Arch A Pathol Anat 1906;185:251–67
  • Hazard JB, Hawk WA, Crile G. Jr, Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 1959;19:152–61
  • Williams ED. Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 1966;19:114–18
  • Randolph GW, Maniar D. Medullary carcinoma of the thyroid. Cancer Control 2000;7:253–61
  • Strosberg JR. Update on the management of unusual neuroendocrine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma. Semin Oncol 2013;40:120–33
  • Campbell MJ, Seib CD, Gosnell J. Vandetanib and the management of advanced medullary thyroid cancer. Curr Opin Oncol 2013;25:39–43
  • LiVolsi VA. C cell hyperplasia/neoplasia. J Clin Endocrinol Metab 1997;82:39–41
  • Quayle FJ, Moley JF. Medullary thyroid carcinoma: management of lymph node metastases. Curr Treatment Opt Oncol 2005;6:347–54
  • Scollo C, Baudin E, Travagli JP, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2003;88:2070–5
  • Figlioli G, Landi S, Romei C, et al. Medullary thyroid carcinoma (MTC) and RET proto-oncogene: mutation spectrum in the familial cases and a meta-analysis of studies on the sporadic form. Mutat Res 2013;752:36–44
  • Brauckhoff M, Machens A, Hess S, et al. Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: an exploratory analysis. Surgery 2008;144:1044–50; discussion 50-3
  • Oberg K. The genetics of neuroendocrine tumors. Semin Oncol 2013;40:37–44
  • Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014;386:2–15
  • Romei C, Cosci B, Renzini G, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol 2011;74:241–7
  • Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–71
  • American Thyroid Association Guidelines Task F, Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565–612
  • Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genetics Med 2011;13:755–64
  • Raue F, Frank-Raue K. Genotype–phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo, Brazil) 2012;67:69–75
  • Yeganeh MZ, Sheikholeslami S, Hedayati M. RET proto oncogene mutation detection and medullary thyroid carcinoma prevention. Asian Pacif J Cancer Prev 2015;16:2107–17
  • Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma The American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Thyroid 2015;25:567–610
  • Costante G, Meringolo D, Durante C, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007;92:450–5
  • Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 2014;14:173–86
  • Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Eng J Med 2003;349:1517–25
  • Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genetics 2012;205:1–11
  • Wohllk N, Schweizer H, Erlic Z, et al. Multiple endocrine neoplasia type 2. Best Pract Res Clin Endocrinol Metab 2010;24:371–87
  • Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985;42:581–8
  • Carter MT, Yome JL, Marcil MN, et al. Conservation of RET proto-oncogene splicing variants and implications for RET isoform function. Cytogenetics Cell Genetics 2001;95:169–76
  • Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development (Cambridge, England) 1993;119:1005–17
  • Meng X, Lindahl M, Hyvonen ME, et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science (New York, NY) 2000;287:1489–93
  • Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 2005;16:441–67
  • Colombo-Benkmann M, Li Z, Riemann B, et al. Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma. Eur J Endocrinol/Eur Feder Endocr Soc 2008;158:811–16
  • de Groot JW, Links TP, Plukker JT, et al. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev 2006;27:535–60
  • Asai N, Iwashita T, Matsuyama M, Takahashi M. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 1995;15:1613–19
  • Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 2001;12:361–73
  • Garcia-Lavandeira M, Diaz-Rodriguez E, Garcia-Rendueles ME, et al. Functional role of the RET dependence receptor, GFRa co-receptors and ligands in the pituitary. Front Hormone Res 2010;38:127–38
  • Santoro M, Melillo RM, Carlomagno F, et al. Minireview: RET: normal and abnormal functions. Endocrinology 2004;145:5448–51
  • Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer 2010;9:449–57
  • Segouffin-Cariou C, Billaud M. Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J Biol Chem 2000;275:3568–76
  • Salehian B, Samoa R. RET gene abnormalities and thyroid disease: who should be screened and when. J Clin Res Pediat Endocrinol 2013;5:70–8
  • Manie S, Santoro M, Fusco A, Billaud M. The RET receptor: function in development and dysfunction in congenital malformation. Trends Genetics: TIG 2001;17:580–9
  • Boikos SA, Stratakis CA. Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment. Histol Histopathol 2008;23:109–16
  • Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab 2008;93:682–7
  • Marx SJ, Stratakis CA. Multiple endocrine neoplasia – introduction. J Internal Med 2005;257:2–5
  • Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. J Am Med Assoc 1996;276:1575–9
  • Hoff AO, Hoff PM. Medullary thyroid carcinoma. Hematol/Oncol Clin N Am 2007;21:475–88
  • Frank-Raue K, Rybicki LA, Erlic Z, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat 2011;32:51–8
  • Machens A, Brauckhoff M, Holzhausen HJ, et al. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 2005;90:3999–4003
  • Quayle FJ, Fialkowski EA, Benveniste R, Moley JF. Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 2007;142:800–5
  • Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genetics 1994;6:70–4
  • Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 2005;15:531–44
  • Toledo RA, Hatakana R, Lourenco DM Jr, et al. Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. Endocr Relat Cancer 2015;22:65–76
  • Iwashita T, Asai N, Murakami H, et al. Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene 1996;12:481–7
  • Miyauchi A, Futami H, Hai N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Resh 1999;90:1–5
  • Gimm O, Marsh DJ, Andrew SD, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 1997;82:3902–4
  • Weitzman SP, Cabanillas ME. The treatment landscape in thyroid cancer: a focus on cabozantinib. Cancer Manag Res 2015;7:265–78
  • Schwartz DL, Rana V, Shaw S, et al. Postoperative radiotherapy for advanced medullary thyroid cancer–local disease control in the modern era. Head Neck 2008;30:883–8
  • Lindsey SC, Ganly I, Palmer F, Tuttle RM. Response to initial therapy predicts clinical outcomes in medullary thyroid cancer. Thyroid: Off J Am Thyroid Assoc 2015;25:242–9
  • Tuttle RM, Haddad RI, Ball DW, et al. Thyroid carcinoma, version 2.2014. J Natl Comprehen Cancer Netw 2014;12:1671–80; quiz 80
  • Frank-Raue K, Buhr H, Dralle H, et al. Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol/Eur Feder Endocr Soc 2006;155:229–36
  • Daumerie C, Maiter D, Gruson D. Serum calcitonin estimation in medullary thyroid cancer: basal or stimulated levels? Thyroid Res 2013;6:S4
  • Pina G, Dubois S, Murat A, et al. Is basal ultrasensitive measurement of calcitonin capable of substituting for the pentagastrin-stimulation test? Clin Endocrinol 2013;78:358–64
  • Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Therapeut 2011;10:2298–308
  • Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002;62:7284–90
  • Herbst RS, Heymach JV, O'Reilly MS, et al. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Invest Drugs 2007;16:239–49
  • Morabito A, Piccirillo MC, Falasconi F, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist 2009;14:378–90
  • Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010;13:1–14
  • Liu XH, Chen GG, Vlantis AC, van Hasselt CA. Iodine mediated mechanisms and thyroid carcinoma. Crit Rev Clin Lab Sci 2009;46:302–18
  • Maier J, van Steeg H, van Oostrom C, et al. Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats and mice. Biochim Biophys Acta 2007;1773:990–9
  • Belfiore A, Russo D, Vigneri R, Filetti S. Graves' disease, thyroid nodules and thyroid cancer. Clin Endocrinol 2001;55:711–18
  • Boltze C, Brabant G, Dralle H, et al. Radiation-induced thyroid carcinogenesis as a function of time and dietary iodine supply: an in vivo model of tumorigenesis in the rat. Endocrinology 2002;143:2584–92
  • Nishikawa A, Ikeda T, Son HY, et al. Pronounced synergistic promotion of N-bis(2-hydroxypropyl)nitrosamine-initiated thyroid tumorigenesis in rats treated with excess soybean and iodine-deficient diets. Toxicol Sci: Off J Soc Toxicol 2005;86:258–63
  • Williams ED, Abrosimov A, Bogdanova T, et al. Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake. Thyroid: Off J Am Thyroid Assoc 2008;18:847–52
  • Dupuy C, Virion A, Ohayon R, et al. Mechanism of hydrogen peroxide formation catalyzed by NADPH oxidase in thyroid plasma membrane. J Biol Chem 1991;266:3739–43
  • Song Y, Driessens N, Costa M, et al. Roles of hydrogen peroxide in thyroid physiology and disease. J Clin Endocrinol Metab 2007;92:3764–73
  • Ohayon R, Boeynaems JM, Braekman JC, et al. Inhibition of thyroid NADPH-oxidase by 2-iodohexadecanal in a cell-free system. Mol Cell Endocrinol 1994;99:133–41
  • Cardoso LC, Martins DC, Figueiredo MD, et al. Ca(2+)/nicotinamide adenine dinucleotide phosphate-dependent H(2)O(2) generation is inhibited by iodide in human thyroids. J Clin Endocrinol Metab 2001;86:4339–43
  • Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J: Off Publ Feder Am Soc Exp Biol 2003;17:1195–214
  • Kupper FC, Carpenter LJ, McFiggans GB, et al. Iodide accumulation provides kelp with an inorganic antioxidant impacting atmospheric chemistry. Proc Natl Acad Sci US A 2008;105:6954–8
  • McClellan J, King MC. Genetic heterogeneity in human disease. Cell 2010;141:210–17
  • Etit D, Faquin WC, Gaz R, et al. Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Arch Path Lab Med 2008;132:1767–73
  • Learoyd DL, Gosnell J, Elston MS, et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol 2005;63:636–41
  • Marsh DJ, Theodosopoulos G, Martin-Schulte K, et al. Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 2003;88:1866–72
  • Pai R, Nehru GA, Samuel P, et al. Mutational analysis of RET proto-oncogene among patients with medullary thyroid carcinoma and 'at risk' carriers from India. Clin Endocrinol 2011;75:571–2
  • Abdelhakim A, Barlier A, Kebbou M, et al. RET genetic screening in patients with medullary thyroid cancer: the Moroccan experience. J Cancer Res Therapeut 2009;5:198–202
  • Benazzouz B, Hafidi A, Benkhira S, et al. C634R mutation of the protooncongene RET and molecular diagnosis in multiple endocrine neoplasia type 2 in a large Moroccan family]. Bull Cancer 2008;95:457–63
  • Benazzouz B, Chraibi A, Doghmi Y, et al. Characterization of RET proto-oncogene C634Y mutation in a Moroccan family with multiple endocrine neoplasia type 2A. Ann Endocrinol 2006;67:21–6
  • Sharma BP, Saranath D. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients. J Biosci 2011;36:603–11
  • Siqueira DR, Romitti M, da Rocha AP, et al. The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma. Endocr Relat Cancer 2010;17:953–63
  • Oliveira MN, Hemerly JP, Bastos AU, et al. The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. Thyroid 2011;21:975–85
  • Tamanaha R, Camacho CP, Pereira AC, et al. Evaluation of RET polymorphisms in a six-generation family with G533C RET mutation: specific RET variants may modulate age at onset and clinical presentation. ClinEndocrinol 2009;71:56–64
  • Jindrichova S, Vcelak J, Vlcek P, et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol 2004;183:257–65
  • Schuffenecker I, Billaud M, Calender A, et al. RET proto-oncogene mutations in French MEN 2A and FMTC families. Human Mol Genetics 1994;3:1939–43
  • Chatal JF, Campion L, Kraeber-Bodere F, et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol: Off J Am Soc Clin Oncol 2006;24:1705–11
  • Guyetant S, Josselin N, Savagner F, et al. C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients. Modern Pathol 2003;16:756–63
  • Goretzki PE, Hoppner W, Dotzenrath C, et al. Genetic and biochemical screening for endocrine disease. World J Surg 1998;22:1202–7
  • Frank-Raue K, Hoppner W, Frilling A, et al. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol Metab 1996;81:1780–3
  • Sarika HL, Papathoma A, Garofalaki M, et al. High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece. Clin Endocrinol 2012;77:857–62
  • Kaldrymides P, Mytakidis N, Anagnostopoulos T, et al. A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol 2006;64:561–6
  • Hedayati M, Zarif Yeganeh M, Sheikhol Eslami S, et al. Predominant RET germline mutations in exons 10, 11, and 16 in Iranian patients with hereditary medullary thyroid carcinoma. J Thyroid Res 2011;2011:264248
  • Alvandi E, Akrami SM, Chiani M, et al. Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population. Thyroid: Off J Am Thyroid Assoc 2011;21:373–82
  • Sheikholeslami Sara ZYM, Hoghooghi RL, Ghadaksaz GH, Hedayati M. Haplotype frequency of G691S/S904S in the RET proto-oncogene in patients with medullary thyroid carcinoma. Iran J Public Health 2014;43:235–40
  • Hedayati M, Nabipour I, Rezaei-Ghaleh N, Azizi F. Germline RET mutations in exons 10 and 11: an Iranian survey of 57 medullary thyroid carcinoma cases. Med J Malaysia 2006;61:564–9
  • Ghazi AA, Bagheri M, Tabibi A, et al. Multiple endocrine neoplasia type 2A in an Iranian family: clinical and genetic studies. Arch Iran Med 2014;17:378–82
  • Majidi M, Haghpanah V, Hedayati M, et al. A family presenting with multiple endocrine neoplasia type 2B: a case report. J Med Case Rep 2011;5:587
  • Zarif Yeganeh M, Sheikholeslami S, Dehbashi Behbahani G, et al. Skewed mutational spectrum of RET proto-oncogene Exon10 in Iranian patients with medullary thyroid carcinoma. Tumour Biol: J the Int Soc Oncodev Biol Med 2015;36:5225–31
  • Romei C, Mariotti S, Fugazzola L, et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol/Eur Feder Endocr Soc 2010;163:301–8
  • Shifrin AL, Ogilvie JB, Stang MT, et al. Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation. Surgery 2010;148:1274–80; discussion 80-1
  • Kameyama K, Okinaga H, Takami H. RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother 2004;58:345–7
  • Gonzalez-Yebra B, Medrano ME, Mantilla A, et al. Penetrance of inherited medullary thyroid carcinoma and genotype-phenotype correlation in a large multiple endocrine neoplasia type 2A family with C634Y RET mutation. Endocr Pathol 2003;14:71–80
  • Chung YJ, Kim HH, Kim HJ, et al. RET proto-oncogene mutations are restricted to codon 634 and 618 in Korean families with multiple endocrine neoplasia 2A. Thyroid 2004;14:813–18
  • Jung J, Uchino S, Lee Y, Park H. A Korean family of familial medullary thyroid cancer with Cys618Ser RET germline mutation. J Korean Med Sci 2010;25:226–9
  • Prazeres HJ, Rodrigues F, Figueiredo P, et al. Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal. Clin Endocrinol 2006;64:659–66
  • Bugalho MJ, Domingues R, Santos JR, et al. Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre. Surgery 2007;141:90–5
  • Moura MM, Cavaco BM, Pinto AE, et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer 2009;100:1777–83
  • Silva AL, Carmo F, Moura MM, et al. Identification and characterization of two novel germline RET variants associated with medullary thyroid carcinoma. Endocrine 2015
  • Moore SW, Zaahl MG. Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET. Pediatr Surg Int 2008;24:521–30
  • Moore SW, Zaahl MG. Chasing the ubiquitous RET proto-oncogene in South African MEN2 families–implications for the surgeon. S Afr J Surg Suid-Afrikaanse tydskrif vir chirurgie 2010;48:127–31
  • Moore SW, Appfelstaedt J, Zaahl MG. Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2. J Pediatr Surg 2007;42:326–32
  • Wohllk N, Becker P, Youlton R, Cote GJ, et al. Germline mutations of the ret proto-oncogene in Chilean patients with hereditary and sporadic medullary thyroid carcinoma. Rev Med Chile 2001;129:713–18
  • Belli S, Storani ME, Dourisboure RJ. Study of RET protooncogene in multiple endocrine neoplasm 2A and in familial medullary thyroid carcinoma. Clinical pathological findings in asymptomatic carriers. Medicina 2003;63:41–5
  • Milos IN, Frank-Raue K, Wohllk N, et al. 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 2008;15:1035–41
  • Sanchez Sobrino P, Paramo Fernandez C, Gil Gil P, et al Phenotype of the C634Y mutation in the RET proto-oncogene in MEN2A: report of a family. Endocrinol Nutrn: Org Soc Espan Endocrinol Nutr 2011;58:229–35

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.