Familial Cancer

, Volume 11, Issue 2, pp 157–165

Hereditary medullary thyroid carcinoma: the management dilemma

  • Ping Zhou
  • Jian Liu
  • Shao-Wen Cheng
  • Bing Wang
  • Rong Yang
  • Ling Peng
Review

Abstract

Hereditary medullary thyroid carcinoma (hereditary MTC) is a rare malignancy, accounting for 25–30% of all MTC. It occurs as part of multiple endocrine neoplasia type 2 (MEN 2). Autosomal dominant gain-of-function mutations in the RET proto-oncogene is the cause of the disease, in which the common mutations are codons 609, 611, 618, 620, 630, 634 and 918. In recent years, the spectrum of RET gene mutations has changed. The classical mutations reduced, whereas the less aggressive mutations increased. Hereditary MTC is a time-dependent disease. Stages of the disorder at diagnosis can significantly influence survival rates. Based on the genotype–phenotype, RET mutations have been classified into four risk levels by American Thyroid Association (ATA) at 2009. The classification system guides the hereditary MTC management, including risk assessment, biochemical screenings and surgical intervention. Though the application of genetic testing and codon-specific phenotypes in hereditary MTC diagnosis is effective with high accuracy, there are some difficulties in implementing RET gene testing as a routine for MTC diagnosis. And most of carriers with RET mutations did not undergo thyroidectomy at the age recommended by the ATA guidelines. The aim of the study is to review the hereditary MTC and discuss the management dilemma.

Keywords

Hereditary medullary thyroid carcinoma RET proto-oncogene Mutation Management Prophylactic thyroidectomy 

Abbreviations

RET

Rearranged during transfection

Hereditary MTC

Hereditary medullary thyroid carcinoma

MEN 2

Multiple endocrine neoplasia type 2

ATA

American Thyroid Association

MTC

Medullary thyroid carcinoma

CCH

C-cell hyperplasia

Pheo

Pheochromocytoma

HPT

Hyperparathyroidism

FMTC

Familial MTC

VUS

Variant of unknown significance

HSCR

Hirschsprung disease

References

  1. 1.
    Clark OH, Kebebew E, Ituarte PHG, Siperstein AE, Duh QY (2000) Medullary thyroid carcinoma—clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88(5):1139–1148PubMedCrossRefGoogle Scholar
  2. 2.
    Hazard JB, Hawk WA, Crile G Jr (1959) Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 19(1):152–161PubMedCrossRefGoogle Scholar
  3. 3.
    Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F, Conte-Devolx B, Dralle H (2003) Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 349(16):1517–1525. doi:10.1056/NEJMoa012915 PubMedCrossRefGoogle Scholar
  4. 4.
    Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) Cancer statistics, 2004. CA Cancer J Clin 54(1):8–29PubMedCrossRefGoogle Scholar
  5. 5.
    Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Mulligan LM et al (1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276(19):1575–1579PubMedCrossRefGoogle Scholar
  6. 6.
    Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L et al (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363(6428):458–460. doi:10.1038/363458a0 PubMedCrossRefGoogle Scholar
  7. 7.
    Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2(7):851–856PubMedCrossRefGoogle Scholar
  8. 8.
    Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A 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(2):237–241PubMedCrossRefGoogle Scholar
  9. 9.
    Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, Mao R (2009) Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat 30(4):548–556. doi:10.1002/humu.20928 PubMedCrossRefGoogle Scholar
  10. 10.
    Peppa M, Boutati E, Kamakari S, Pikounis V, Peros G, Panayiotides IG, Economopoulos T, Raptis SA, 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(6):767–771. doi:10.1530/eje-08-0476 PubMedCrossRefGoogle Scholar
  11. 11.
    Kaldrymides P, Mytakidis N, Anagnostopoulos T, Vassiliou M, Tertipi A, Zahariou M, Rampias T, Koutsodontis G, Konstantopoulou I, Ladopoulou A, Bei T, Yannoukakos D (2006) A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol (Oxf) 64(5):561–566. doi:10.1111/j.1365-2265.2006.02509.x CrossRefGoogle Scholar
  12. 12.
    Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, Zajac JD, Robinson BG, Eng C (1997) 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 82(11):3902–3904PubMedCrossRefGoogle Scholar
  13. 13.
    Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallion AS, Hodgson S, Clarke S, Mondellini P, Leyland J, Pierotti MA, Whittaker J, Taylor SS, Bongarzone I, Ponder BA (2006) RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 66(20):10179–10187. doi:10.1158/0008-5472.can-06-0884 PubMedCrossRefGoogle Scholar
  14. 14.
    Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki N, Kosugi S, Sugano K, Yamaguchi K (1999) 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 Res 90(1):1–5PubMedCrossRefGoogle Scholar
  15. 15.
    Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, Qiao S, Ichihara M, Takahashi M (2000) A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun 268(3):804–808. doi:10.1006/bbrc.2000.2227 PubMedCrossRefGoogle Scholar
  16. 16.
    Frank-Raue K, Hoppner W, Frilling A, Kotzerke J, Dralle H, Haase R, Mann K, Seif F, Kirchner R, Rendl J, Deckart HF, Ritter MM, Hampel R, Klempa J, Scholz GH, Raue F (1996) 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 81(5):1780–1783PubMedCrossRefGoogle Scholar
  17. 17.
    Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, Sherman SI, Gagel RF, Lee JE, Evans DB (2003) Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 138(4):409–416. doi:10.1001/archsurg.138.4.409 discussion 416PubMedCrossRefGoogle Scholar
  18. 18.
    Frank-Raue K, Rondot S, Raue F (2010) Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Mol Cell Endocrinol 322(1–2):2–7. doi:10.1016/j.mce.2010.01.012 PubMedCrossRefGoogle Scholar
  19. 19.
    Frank-Raue K, Rondot S, Schulze E, Raue F (2007) Change in the spectrum of RET mutations diagnosed between 1994 and 2006. Clin Lab 53(5–6):273–282PubMedGoogle Scholar
  20. 20.
    Frank-Raue K, Dohring J, Scheumann G, Rondot S, Lorenz A, Schulze E, Dralle H, Raue F, Leidig-Bruckner G (2010) New mutations in the RET protooncogene-L881 V—associated with medullary thyroid carcinoma and -R770Q—in a patient with mixed medullar/follicular thyroid tumour. Exp Clin Endocrinol Diabetes 118(8):550–553. doi:10.1055/s-0029-1241851 PubMedCrossRefGoogle Scholar
  21. 21.
    Castellone MD, Verrienti A, Magendra Rao D, Sponziello M, Fabbro D, Muthu M, Durante C, Maranghi M, Damante G, Pizzolitto S, Costante G, Russo D, Santoro M, Filetti S (2010) A novel de novo germ-line V292 M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization. Clin Endocrinol (Oxf) 73(4):529–534. doi:10.1111/j.1365-2265.2009.03757.x Google Scholar
  22. 22.
    Pazaitou-Panayiotou K, Giatzakis C, Koutsodontis G, Vratimos A, Chrisoulidou A, Konstantinidis T, Kamakari S (2010) Identification of two novel mutations in the RET proto-oncogene in the same family. Thyroid 20(4):401–406. doi:10.1089/thy.2009.0262 PubMedCrossRefGoogle Scholar
  23. 23.
    Machens A, Dralle H (2008) Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf) 69(1):81–87. doi:10.1111/j.1365-2265.2007.03153.x CrossRefGoogle Scholar
  24. 24.
    Machens A, Lorenz K, Dralle H (2009) Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med 266(1):114–125. doi:10.1111/j.1365-2796.2009.02113.x PubMedCrossRefGoogle Scholar
  25. 25.
    Romei C, Mariotti S, Fugazzola L, Taccaliti A, Pacini F, Opocher G, Mian C, Castellano M, degli Uberti E, Ceccherini I, Cremonini N, Seregni E, Orlandi F, Ferolla P, Puxeddu E, Giorgino F, Colao A, Loli P, Bondi F, Cosci B, Bottici V, Cappai A, Pinna G, Persani L, Verga U, Boscaro M, Castagna MG, Cappelli C, Zatelli MC, Faggiano A, Francia G, Brandi ML, Falchetti A, Pinchera A, Elisei R (2010) 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 163(2):301–308. doi:10.1530/eje-10-0333 PubMedCrossRefGoogle Scholar
  26. 26.
    Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr (2009) Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19(6):565–612. doi:10.1089/thy.2008.0403 PubMedCrossRefGoogle Scholar
  27. 27.
    Bugalho MJ, Domingues R, Santos JR, Catarino AL, Sobrinho L (2007) Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre. Surgery 141(1):90–95. doi:10.1016/j.surg.2006.03.025 PubMedCrossRefGoogle Scholar
  28. 28.
    Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska K, Krassowski J, Scieglinska D, Fiszer-Kierzkowska A, Lange D, Kula D, Zeman M, Roskosz J, Kukulska A, Krawczyk Z, Jarzab B (2001) Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol 19(5):1374–1380PubMedGoogle Scholar
  29. 29.
    Elisei R, Romei C, Cosci B, Agate L, Bottici V, Molinaro E, Sculli M, Miccoli P, Basolo F, Grasso L, Pacini F, Pinchera A (2007) RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocr Metab 92(12):4725–4729. doi:10.1210/Jc.2007-1005 PubMedCrossRefGoogle Scholar
  30. 30.
    Allen SM, Bodenner D, Suen JY, Richter GT (2009) Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma. Laryngoscope 119(7):1303–1311. doi:10.1002/lary.20299 PubMedCrossRefGoogle Scholar
  31. 31.
    Roman S, Lin R, Sosa JA (2006) Prognosis of medullary thyroid carcinoma—demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107(9):2134–2142. doi:10.1002/Cncr.22244 PubMedCrossRefGoogle Scholar
  32. 32.
    Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK, Lam KS (2009) Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing. Hong Kong Med J 15(5):326–331PubMedGoogle Scholar
  33. 33.
    Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL (2008) Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid 18(12):1261–1268. doi:10.1089/thy.2007.0414 PubMedCrossRefGoogle Scholar
  34. 34.
    Spinelli C, Di Giacomo M, Costanzo S, Elisei R, Miccoli P (2010) Role of RET codonic mutations in the surgical management of medullary thyroid carcinoma in pediatric age multiple endocrine neoplasm type 2 syndromes. J Pediatr Surg 45(8):1610–1616. doi:10.1016/j.jpedsurg.2010.03.019 PubMedCrossRefGoogle Scholar
  35. 35.
    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(2):229–236. doi:10.1530/eje.1.02216 PubMedCrossRefGoogle Scholar
  36. 36.
    Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA Jr (2005) Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353(11):1105–1113. doi:10.1056/NEJMoa043999 PubMedCrossRefGoogle Scholar
  37. 37.
    Schellhaas E, Konig C, Frank-Raue K, Buhr HJ, Hotz HG (2009) Long-term outcome of “prophylactic therapy” for familial medullary thyroid cancer. Surgery 146(5):906–912. doi:10.1016/j.surg.2009.06.007 PubMedCrossRefGoogle Scholar
  38. 38.
    Ukkat J, Gimm O, Brauckhoff M, Bilkenroth U, Dralle H (2004) Single center experience in primary surgery for medullary thyroid carcinoma. World J Surg 28(12):1271–1274. doi:10.1007/s00268-004-7608-9 PubMedCrossRefGoogle Scholar
  39. 39.
    Raval MV, Sturgeon C, Bentrem DJ, Elaraj DM, Stewart AK, Winchester DJ, Ko CY, Reynolds M (2010) Influence of lymph node metastases on survival in pediatric medullary thyroid cancer. J Pediatr Surg 45(10):1947–1954. doi:10.1016/j.jpedsurg.2010.06.013 PubMedCrossRefGoogle Scholar
  40. 40.
    Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle B, Kaserer K, Waldhausl W, Vierhapper H (2005) Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? J Clin Endocrinol Metab 90(11):6232–6236. doi:10.1210/jc.2005-1278 PubMedCrossRefGoogle Scholar
  41. 41.
    Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, Toledo SP, Toledo RA, Tavares MR, Alevizaki M, Mian C, Siggelkow H, Hufner M, Wohllk N, Opocher G, Dvorakova S, Bendlova B, Czetwertynska M, Skasko E, Barontini M, Sanso G, Vorlander C, Maia AL, Patocs A, Links TP, de Groot JW, Kerstens MN, Valk GD, Miehle K, Musholt TJ, Biarnes J, Damjanovic S, Muresan M, Wuster C, Fassnacht M, Peczkowska M, Fauth C, Golcher H, Walter MA, Pichl J, Raue F, Eng C, Neumann HP (2011) Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat 32(1):51–58. doi:10.1002/humu.21385 PubMedCrossRefGoogle Scholar
  42. 42.
    Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs A, Robledo M, Biarnes J, Barontini M, Links TP, de Groot JW, Dvorakova S, Peczkowska M, Rybicki LA, Sullivan M, Raue F, Zosin I, Eng C, Neumann HP (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(4):1035–1041. doi:10.1677/erc-08-0105 PubMedCrossRefGoogle Scholar
  43. 43.
    Raue F, Frank-Raue K (2010) Update multiple endocrine neoplasia type 2. Fam Cancer 9(3):449–457. doi:10.1007/s10689-010-9320-2 PubMedCrossRefGoogle Scholar
  44. 44.
    Bergenfelz A, Jansson S, Kristoffersson A, Martensson H, Reihner E, Wallin G, Lausen I (2008) Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg 393(5):667–673. doi:10.1007/s00423-008-0366-7 PubMedCrossRefGoogle Scholar
  45. 45.
    Grubbs EG, Waguespack SG, Rich TA, Xing Y, Ying AK, Evans DB, Lee JE, Perrier ND (2010) Do the recent American Thyroid Association (ATA) Guidelines accurately guide the timing of prophylactic thyroidectomy in MEN2A? Surgery 148(6):1302–1309. doi:10.1016/j.surg.2010.09.020 Discussion 1309–1310PubMedCrossRefGoogle Scholar
  46. 46.
    Richter GT, Allen SM, Bodenner D, Suen JY (2009) Diagnostic and surgical Dilemmas in hereditary medullary thyroid carcinoma. Laryngoscope 119(7):1303–1311. doi:10.1002/Lary.20299 PubMedCrossRefGoogle Scholar
  47. 47.
    Fazioli F, Piccinini G, Appolloni G, Bacchiocchi R, Palmonella G, Recchioni R, Pierpaoli E, Silvetti F, Scarpelli M, Bruglia M, Melillo RM, Santoro M, Boscaro M, Taccaliti A (2008) A new germline point mutation in Ret exon 8 (cys515ser) in a family with medullary thyroid carcinoma. Thyroid 18(7):775–782. doi:10.1089/thy.2007.0365 PubMedCrossRefGoogle Scholar
  48. 48.
    Da Silva AM, Maciel RM, Da Silva MR, Toledo SR, De Carvalho MB, Cerutti JM (2003) A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab 88(11):5438–5443PubMedCrossRefGoogle Scholar
  49. 49.
    Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E, Ponder MA, Frilling A, Jackson CE, Lehnert H et al (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6(1):70–74. doi:10.1038/ng0194-70 PubMedCrossRefGoogle Scholar
  50. 50.
    Hoppner W, Dralle H, Brabant G (1998) Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mutat Suppl 1:S128–S130CrossRefGoogle Scholar
  51. 51.
    Maschek W, Pichler R, Rieger R, Weinhausel A, Berg J (2002) A new identified germline mutation of the RET proto-oncogene responsible for familial medullary thyroid carcinoma in co-existence with a hyperfunctioning autonomous nodule. Clin Endocrinol (Oxf) 56(6):823CrossRefGoogle Scholar
  52. 52.
    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(2):257–265. doi:10.1677/joe.1.05838 PubMedCrossRefGoogle Scholar
  53. 53.
    Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Hoppner W (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(3):770–774PubMedCrossRefGoogle Scholar
  54. 54.
    Fink M, Weinhusel A, Niederle B, Haas OA (1996) Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. Study Group Multiple Endocrine Neoplasia Austria (SMENA). Int J Cancer 69(4):312–316. doi:10.1002/(sici)1097-0215(19960822)69:4<312:aid-ijc13>3.0.co;2-7 PubMedCrossRefGoogle Scholar
  55. 55.
    Smith DP, Houghton C, Ponder BA (1997) Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15(10):1213–1217. doi:10.1038/sj.onc.1201481 PubMedCrossRefGoogle Scholar
  56. 56.
    Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, Colantuoni V, Buys CH (1997) A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 82(12):4176–4178PubMedCrossRefGoogle Scholar
  57. 57.
    Jimenez C, Dang GT, Schultz PN, El-Naggar A, Shapiro S, Barnes EA, Evans DB, Vassilopoulou-Sellin R, Gagel RF, Cote GJ, Hoff AO (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(7):3521–3526. doi:10.1210/jc.2004-0073 PubMedCrossRefGoogle Scholar
  58. 58.
    Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L, Passannanti P, Viola D, Biagini A, Basolo F, Ugolini C, Materazzi G, Pinchera A, Vitti P, Elisei R (2011) 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 (Oxf) 74(2):241–247. doi:10.1111/j.1365-2265.2010.03900.x CrossRefGoogle Scholar
  59. 59.
    Zhang XN, Qi XP, Ma JM, Du ZF, Ying RB, Fei J, Jin HY, Han JS, Wang JQ, Chen XL, Chen CY, Liu WT, Lu JJ, Zhang JG (2011) RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary Thyroid carcinoma family. PLoS One 6(5). doi:10.1371/journal.pone.0020353
  60. 60.
    Park H, Jung J, Uchino S, Lee Y (2010) A Korean family of familial medullary thyroid cancer with Cys618Ser RET germline mutation. J Korean Med Sci 25(2):226–229. doi:10.3346/jkms.2010.25.2.226 PubMedCrossRefGoogle Scholar
  61. 61.
    Calva D, O’Dorisio TM, Sue O’Dorisio M, Lal G, Sugg S, Weigel RJ, Howe JR (2009) When is prophylactic thyroidectomy indicated for patients with the RET codon 609 mutation? Ann Surg Oncol 16(8):2237–2244. doi:10.1245/s10434-009-0524-3 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Ping Zhou
    • 1
  • Jian Liu
    • 4
  • Shao-Wen Cheng
    • 2
  • Bing Wang
    • 1
  • Rong Yang
    • 1
  • Ling Peng
    • 3
  1. 1.Department of Surgical Oncology, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
  2. 2.Trauma Center, The Affiliated Hospital of Hainan Medical CollegeHaikouChina
  3. 3.Department of Medical Oncology, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
  4. 4.Department of Surgical OncologyHangzhou Hospital of Traditional Chinese MedicineHangzhouChina

Personalised recommendations