Skip to main content
SpringerLink
Log in

Recent Developments in the Molecular Biology of the Thyroid

  • Chapter
Endocrine Pathology

  • 155 Accesses

Abstract

The last decade has seen a significant expansion in our understanding of the molecular biology of the thyroid. It has become clear that the molecular landscape of thyroid tumors arising from follicular epithelium is dominated by chromosomal rearrangements, which are otherwise prevalent in hematologic malignancies and sarcomas, but not in other types of epithelial neoplasms. The identification of the gene responsible for the familial forms of medullary carcinomas, originated from thyroid C-cell tumors, has led to a dramatic change in the management of patients with this disease, and is one of the first examples of preventive surgery performed solely on the basis of molecular genetic testing. The progress in molecular biology is expected to permeate into virtually all aspects of thyroid pathology and provide significant assistance in the diagnosis of thyroid tumors, in the determination of tumor prognosis, as well as to serve as an additional aid for proper classification of thyroid tumors. In this respect, it is important to realize that the thyroid gland represents a unique model of tumorigenesis, as thyroid follicular cells give rise to the malignant tumors with a widely variable biological behavior. Indeed, well-differentiated papillary, follicular, and Hürthle cell carcinomas have an overall favorable prognosis; poorly differentiated carcinoma behaves in a more aggressive manner, while anaplastic carcinoma is one of the deadliest human malignancies. In this chapter, we follow the general classification of thyroid tumors and summarize molecular alterations identified in each type of thyroid malignant and benign neoplasms.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 2000; 89: 202–217.

    CAS  Google Scholar 

  2. Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990; 19: 545–576.

    CAS  PubMed  Google Scholar 

  3. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer 1998; 83: 2638–2648.

    CAS  PubMed  Google Scholar 

  4. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985; 42: 581–588.

    CAS  PubMed  Google Scholar 

  5. Takahashi M. Structure and expression of the ret transforming gene. IARC Sci Publ 1988: 189–197.

    Google Scholar 

  6. Schuchardt A, D’Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 1994; 367: 380–383.

    CAS  PubMed  Google Scholar 

  7. Airaksinen MS, Titievsky A, Saarma M. GDNF family neurotrophic factor signaling: four masters, one servant? Mol Cell Neurosci 1999; 13: 313–325.

    CAS  PubMed  Google Scholar 

  8. Jing S, Wen D, Yu Y, et al. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 1996; 85: 1113–1124.

    CAS  PubMed  Google Scholar 

  9. Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990; 60: 557–563.

    CAS  PubMed  Google Scholar 

  10. Santoro M, Dathan NA, Berlingieri MT, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RETprotooncogene in a human thyroid papillary carcinoma. Oncogene 1994; 9: 509–516.

    CAS  PubMed  Google Scholar 

  11. Bongarzone I, Butti MG, Coronelli S, et al. Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 1994; 54: 2979–2985.

    CAS  PubMed  Google Scholar 

  12. Pierotti MA, Santoro M, Jenkins RB, et al. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S 170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA 1992; 89: 1616–1620.

    CAS  PubMed  Google Scholar 

  13. Minoletti F, Butti MG, Coronelli S, et al. The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Genes Chromosomes Cancer 1994; 11: 51–57.

    CAS  PubMed  Google Scholar 

  14. Bongarzone I, Monzini N, Borrello MG, et al. Molecular characterization of a thyroid tumor-speciifc transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol Cell Biol 1993; 13: 358–366.

    CAS  PubMed  Google Scholar 

  15. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM. Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5. Cancer Res 1998; 58: 198–203.

    CAS  PubMed  Google Scholar 

  16. Klugbauer S, Rabes HM. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 1999;18:4388– 4393.

    Google Scholar 

  17. Nakata T, Kitamura Y, Shimizu K, et al. Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q1 1;p13) in a papillary thyroid carcinoma. Genes Chromosomes Cancer 1999; 25: 97–103.

    CAS  PubMed  Google Scholar 

  18. Klugbauer S, Jauch A, Lengfelder E, Demidchik E, Rabes HM. A novel type of RET rearrangement (PTC8) in childhood papillary thyroid carcinomas and characterization of the involved gene (RFG8). Cancer Res 2000; 60: 7028–7032.

    CAS  PubMed  Google Scholar 

  19. Salassidis K, Bruch J, Zitzelsberger H, Lengfelder E, Kellerer AM, Bauchinger M. Translocation t(10;14)(q1 1.2:q22.1) fusing the kinetin to the RET gene creates a novel rearranged form (PTC8) of the RET proto-oncogene in radiation-induced childhood papillary thyroid carcinoma. Cancer Res 2000; 60: 2786–2789.

    CAS  PubMed  Google Scholar 

  20. Corvi R, Berger N, Balczon R, Romeo G. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 2000; 19: 4236–4242.

    CAS  PubMed  Google Scholar 

  21. Tong Q, Xing S, Jhiang SM. Leucine zipper-mediated dimerization is essential for the PTC1 oncogenic activity. J Biol Chem 1997; 272: 9043–9047.

    CAS  PubMed  Google Scholar 

  22. Jhiang SM. The RET proto-oncogene in human cancers. Oncogene 2000; 19: 5590–5597.

    CAS  PubMed  Google Scholar 

  23. Monaco C, Visconti R, Barone MV, et al. The RFG oligomerization domain mediates kinase activation and re-localization of the RET/ PTC3 oncoprotein to the plasma membrane. Oncogene 2001; 20: 599–608.

    CAS  PubMed  Google Scholar 

  24. Santoro M, Melillo RM, Grieco M, Berlingieri MT, Vecchio G, Fusco A. The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 1993; 4: 77–84.

    CAS  PubMed  Google Scholar 

  25. Jhiang SM, Sagartz JE, Tong Q, et al. Targeted expression of the ret/ PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 1996; 137: 375–378.

    CAS  PubMed  Google Scholar 

  26. Santoro M, Chiappetta G, Cerrato A, et al. Development of thyroid papillary carcinomas secondary to tissue-speciifc expression of the RET/ PTC1 oncogene in transgenic mice. Oncogene 1996; 12: 1821–1826.

    CAS  PubMed  Google Scholar 

  27. Powell DJ, Jr., Russell J, Nibu K, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 1998; 58: 5523–5528.

    CAS  PubMed  Google Scholar 

  28. Fischer AH, Bond JA, Taysavang P, Battles OE, Wynford-Thomas D. Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathol 1998; 153: 1443–1450.

    CAS  PubMed  Google Scholar 

  29. Santoro M, Sabino N, Ishizaka Y, et al. Involvement of RET oncogene in human tumours: speciifcity of RET activation to thyroid tumours. Br J Cancer 1993; 68: 460–464.

    CAS  PubMed  Google Scholar 

  30. Santoro M, Carlomagno F, Hay ID, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992; 89: 1517–1522.

    CAS  PubMed  Google Scholar 

  31. Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation deifnes a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 1998; 4: 287–294.

    CAS  PubMed  Google Scholar 

  32. Papotti M, Volante M, Giuliano A, et al. RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 2000; 24: 1615–1621.

    CAS  PubMed  Google Scholar 

  33. Cheung CC, Boerner SL, MacMillan CM, Ramyar L, Asa SL. Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 2000; 24: 1622–1626.

    CAS  PubMed  Google Scholar 

  34. Rosai J, Carcangiu ML, DeLellis RA. Tumors of the Thyroid. Washington, DC: Armed Forces Institute of Pathology, 1992.

    Google Scholar 

  35. Ishizaka Y, Kobayashi S, Ushijima T, Hirohashi S, Sugimura T, Nagao M. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene 1991; 6: 1667–1672.

    CAS  PubMed  Google Scholar 

  36. Bounacer A, Wicker R, Caillou B, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 1997; 15: 1263–1273.

    CAS  PubMed  Google Scholar 

  37. Wirtschafter A, Schmidt R, Rosen D, et al. Expression of the RET/ PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope 1997; 107: 95–100.

    CAS  PubMed  Google Scholar 

  38. Cinti R, Yin L, Ilc K, et al. RET rearrangements in papillary thyroid carcinomas and adenomas detected by interphase FISH. Cytogenet Cell Genet 2000; 88: 56–61.

    CAS  PubMed  Google Scholar 

  39. Sheils OM, O’Eary JJ, Uhlmann V, Lattich K, Sweeney EC. ret/ PTC-1 activation in Hashimoto thyroiditis. Int J Surg Pathol 2000; 8: 185–189.

    CAS  PubMed  Google Scholar 

  40. Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 2001; 86: 3211–3216.

    CAS  PubMed  Google Scholar 

  41. Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol 2002; 13: 3–16.

    CAS  PubMed  Google Scholar 

  42. Jhiang SM, Caruso DR, Gilmore E, et al. Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene 1992; 7: 1331–1337.

    CAS  PubMed  Google Scholar 

  43. Lam AK, Montone KT, Nolan KA, Livolsi VA. Ret oncogene activation in papillary thyroid carcinoma: prevalence and implication on the histological parameters. Hum Pathol 1998; 29: 565–568.

    CAS  PubMed  Google Scholar 

  44. Nikiforova MN, Caudill CM, Biddinger BW, Nikiforov YE. Prevalence of RET/PTC rearrangements in Hashimoto’s thyroiditis and papillary thyroid carcinomas. Int J Surg Pathol 2002; 10: 15–22.

    CAS  PubMed  Google Scholar 

  45. Sugg SL, Ezzat S, Zheng L, Freeman JL, Rosen IB, Asa SL. Oncogene profile of papillary thyroid carcinoma. Surgery 1999; 125: 46–52.

    CAS  PubMed  Google Scholar 

  46. Bongarzone I, Fugazzola L, Vigneri P, et al. Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. J Clin Endocrinol Metab 1996; 81: 2006–2009.

    CAS  PubMed  Google Scholar 

  47. Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res 1998; 4: 223–228.

    CAS  PubMed  Google Scholar 

  48. Zou M, Shi Y, Farid NR. Low rate of ret proto-oncogene activation (PTC/retTPC) in papillary thyroid carcinomas from Saudi Arabia. Cancer 1994; 73: 176–180.

    CAS  PubMed  Google Scholar 

  49. Chua EL, Wu WM, Tran KT, et al. Prevalence and distribution of ret/ptc 1, 2, and 3 in papillary thyroid carcinoma in New Caledonia and Australia. J Clin Endocrinol Metab 2000; 85: 2733–2739.

    CAS  PubMed  Google Scholar 

  50. Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997; 57: 1690–1694.

    CAS  PubMed  Google Scholar 

  51. Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL, Tuttle RM. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab 2000; 85: 1170–1175.

    CAS  PubMed  Google Scholar 

  52. Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? J Pathol 1998; 185: 71–78.

    CAS  PubMed  Google Scholar 

  53. Fugazzola L, Pilotti S, Pinchera A, et al. Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res 1995; 55: 5617–5620.

    CAS  PubMed  Google Scholar 

  54. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene 1995; 11: 2459–2467.

    CAS  PubMed  Google Scholar 

  55. Smida J, Salassidis K, Hieber L, et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int J Cancer 1999; 80: 32–38.

    CAS  PubMed  Google Scholar 

  56. Rabes HM, Demidchik EP, Sidorow JD, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 2000; 6: 1093–1103.

    CAS  PubMed  Google Scholar 

  57. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM. Molecular analysis of new subtypes of ELE/RET rearrangements, their reciprocal transcripts and breakpoints in papillary thyroid carcinomas of children after Chernobyl. Oncogene 1998; 16: 671–675.

    CAS  PubMed  Google Scholar 

  58. Rabes HM. Gene rearrangements in radiation-induced thyroid carcinogenesis. Med Pediatr Oncol 2001; 36: 574–582.

    CAS  PubMed  Google Scholar 

  59. Ito T, Seyama T, Iwamoto KS, et al. In vitro irradiation is able to cause RET oncogene rearrangement. Cancer Res 1993; 53: 2940–2943.

    CAS  PubMed  Google Scholar 

  60. Mizuno T, Kyoizumi S, Suzuki T, Iwamoto KS, Seyama T. Continued expression of a tissue speciifc activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. Oncogene 1997; 15: 1455–1460.

    CAS  PubMed  Google Scholar 

  61. Mizuno T, Iwamoto KS, Kyoizumi S, et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 2000; 19: 438–443.

    CAS  PubMed  Google Scholar 

  62. Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 2000; 290: 138–141.

    CAS  PubMed  Google Scholar 

  63. Viglietto G, Chiappetta G, Martinez-Tello FJ, et al. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 1995; 11: 1207–1210.

    CAS  PubMed  Google Scholar 

  64. Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL. Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 1998; 83: 4116–4122.

    CAS  PubMed  Google Scholar 

  65. Basolo F, Giannini R, Monaco C, et al. Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 2002; 160: 247–254.

    CAS  PubMed  Google Scholar 

  66. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL. Molecular basis of Hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 2000; 85: 878–882.

    CAS  PubMed  Google Scholar 

  67. Cetta F, Olschwang S, Petracci M, et al. Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection. World J Surg 1998; 22: 1231–1236.

    CAS  PubMed  Google Scholar 

  68. Soravia C, Sugg SL, Berk T, et al. Familial adenomatous polyposisassociated thyroid cancer: a clinical, pathological, and molecular genetics study. Am J Pathol 1999; 154: 127–135.

    CAS  PubMed  Google Scholar 

  69. Thomas GA, Bunnell H, Cook HA, et al. High prevalence of RET/ PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/ PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 1999; 84: 4232–4238.

    CAS  PubMed  Google Scholar 

  70. Nikiforov YE, Erickson LA, Nikiforova MN, Caudill CM, Lloyd RV. Solid variant of papillary thyroid carcinoma: incidence, clinical-pathologic characteristics, molecular analysis, and biologic behavior. Am J Surg Pathol 2001; 25: 1478–1484.

    CAS  PubMed  Google Scholar 

  71. Mayr B, Brabant G, Goretzki P, Ruschoff J, Dietmaier W, Dralle H. ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab 1997; 82: 1306–1307.

    CAS  PubMed  Google Scholar 

  72. Nikiforov YE, Bove KE, Rowland JM, Fagin JA. RET/PTC1 and RET/PTC3 rearrangements are associated with different biological behavior of papillary thyroid carcinoma (Abstract). Mod Pathol 2000; 13: 73A.

    Google Scholar 

  73. Sagartz JE, Jhiang SM, Tong Q, Capen CC. Thyroid-stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene. Lab Invest 1997; 76: 307–318.

    CAS  PubMed  Google Scholar 

  74. Barbacid M, Lamballe F, Pulido D, Klein R. The trk family of tyrosine protein kinase receptors. Biochim Biophys Acta 1991; 1072: 115–127.

    CAS  PubMed  Google Scholar 

  75. Pierotti MA, Bongarzone I, Borello MG, Greco A, Pilotti S, Sozzi G. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 1996; 16: 1–14.

    CAS  PubMed  Google Scholar 

  76. Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 1986; 319: 743–748.

    CAS  PubMed  Google Scholar 

  77. Radice P, Sozzi G, Miozzo M, et al. The human tropomyosin gene involved in the generation of the TRK oncogene maps to chromosome 1q31. Oncogene 1991; 6: 2145–2148.

    CAS  PubMed  Google Scholar 

  78. Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C, Della Porta G. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene 1992; 7: 237–242.

    CAS  PubMed  Google Scholar 

  79. Miranda C, Minoletti F, Greco A, Sozzi G, Pierotti MA. Reifned localization of the human TPR gene to chromosome 1q25 by in situ hybridization. Genomics 1994; 23: 714–715.

    CAS  PubMed  Google Scholar 

  80. Greco A, Mariani C, Miranda C, et al. The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain. Mol Cell Biol 1995; 15: 6118–6127.

    CAS  PubMed  Google Scholar 

  81. Russell JP, Powell DJ, Cunnane M, et al. The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium. Oncogene 2000; 19: 5729–5735.

    CAS  PubMed  Google Scholar 

  82. Musholt TJ, Musholt PB, Khaladj N, Schulz D, Scheumann GF, Klempnauer J. Prognostic signiifcance of RET and NTRK1 rear-rangements in sporadic papillary thyroid carcinoma. Surgery 2000; 128: 984–993.

    CAS  PubMed  Google Scholar 

  83. Lemoine NR, Mayall ES, Wyllie FS, et al. Activated ras oncogenes in human thyroid cancers. Cancer Res 1988; 48: 4459–4463.

    CAS  PubMed  Google Scholar 

  84. Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol 1990; 4: 1474–1479.

    CAS  PubMed  Google Scholar 

  85. Karga H, Lee JK, Vickery AL Jr, Thor A, Gaz RD, Jameson JL. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991; 73: 832–836.

    CAS  PubMed  Google Scholar 

  86. Manenti G, Pilotti S, Re FC, Della Porta G, Pierotti MA. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer 1994; 30A: 987–993.

    Google Scholar 

  87. Hara H, Fulton N, Yashiro T, Ito K, DeGroot LJ, Kaplan EL. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery 1994; 116: 1010–1016.

    CAS  PubMed  Google Scholar 

  88. Basolo F, Pisaturo F, Pollina LE, et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid 2000; 10: 19–23.

    CAS  PubMed  Google Scholar 

  89. Motoi N, Sakamoto A, Yamochi T, Horiuchi H, Motoi T, Machinami R. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract 2000; 196: 1–7.

    CAS  PubMed  Google Scholar 

  90. Suarez HG, du Villard JA, Severino M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990; 5: 565–570.

    CAS  PubMed  Google Scholar 

  91. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene 2000; 19: 5582–5589.

    CAS  PubMed  Google Scholar 

  92. Di Renzo MF, Olivero M, Ferro S, et al. Overexpression of the cMET/HGF receptor gene in human thyroid carcinomas. Oncogene 1992; 7: 2549–2553.

    PubMed  Google Scholar 

  93. Huang Y, Prasad M, Lemon WJ, et al. Gene expression in papillary thyroid carcinoma reveals highly consistent proifles. Proc Natl Acad Sci USA 2001; 98: 15044–15049.

    CAS  PubMed  Google Scholar 

  94. Prat M, Narsimhan RP, Crepaldi T, Nicotra MR, Natali PG, Comoglio PM. The receptor encoded by the human c-MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer 1991; 49: 323–328.

    CAS  PubMed  Google Scholar 

  95. Ivan M, Bond JA, Prat M, Comoglio PM, Wynford-Thomas D. Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells. Oncogene 1997; 14: 2417–2423.

    CAS  PubMed  Google Scholar 

  96. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993; 328: 553–559.

    CAS  PubMed  Google Scholar 

  97. Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989; 4: 159–164.

    CAS  PubMed  Google Scholar 

  98. Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf) 1999; 50: 529–535.

    CAS  Google Scholar 

  99. Schark C, Fulton N, Jacoby RF, Westbrook CA, Straus FH, 2nd, Kaplan EL. N-ras 61 oncogene mutations in Hurthle cell tumors. Surgery 1990;108:994–999; discussion 999–1000.

    Google Scholar 

  100. Tallini G, Hsueh A, Liu S, Garcia-Rostan G, Speicher MR, Ward DC. Frequent chromosomal DNA unbalance in thyroid oncocytic (Hurthle cell) neoplasms detected by comparative genomic hybridization. Lab Invest 1999; 79: 547–555.

    CAS  PubMed  Google Scholar 

  101. Krohn K, Reske A, Ackermann F, Muller A, Paschke R. Ras mutations are rare in solitary cold and toxic thyroid nodules. Clin Endocrinol (Oxf) 2001; 55: 241–248.

    CAS  Google Scholar 

  102. Shi YF, Zou MJ, Schmidt H, et al. High rates of ras codon 61 mutation in thyroid tumors in an iodide-deifcient area. Cancer Res 1991; 51: 2690–2693.

    CAS  PubMed  Google Scholar 

  103. Lemoine NR, Mayall ES, Williams ED, Thurston V, Wynford-Thomas D. Agent-speciifc ras oncogene activation in rat thyroid tumours. Oncogene 1988; 3: 541–544.

    CAS  PubMed  Google Scholar 

  104. Wright PA, Williams ED, Lemoine NR, Wynford-Thomas D. Radiation-associated and ‘spontaneous’ human thyroid carcino-mas show a different pattern of ras oncogene mutation. Oncogene 1991; 6: 471–473.

    CAS  PubMed  Google Scholar 

  105. Challeton C, Bounacer A, Du Villard JA, et al. Pattern of ras and gsp oncogene mutations in radiation-associated human thyroid tumors. Oncogene 1995; 11: 601–603.

    CAS  PubMed  Google Scholar 

  106. Nikiforov YE, Nikiforova MN, Gnepp DR, Fagin JA. Prevalence of mutations of ras and p53 in benign and malignant thyroid tumors from children exposed to radiation after the Chernobyl nuclear accident. Oncogene 1996; 13: 687–693.

    CAS  PubMed  Google Scholar 

  107. Suchy B, Waldmann V, Klugbauer S, Rabes HM. Absence of RAS and p53 mutations in thyroid carcinomas of children after Chernobyl in contrast to adult thyroid tumours. Br J Cancer 1998; 77: 952–955.

    CAS  PubMed  Google Scholar 

  108. Santelli G, de Franciscis V, Portella G, et al. Production of trans-genic mice expressing the Ki-ras oncogene under the control of a thyroglobulin promoter. Cancer Res 1993; 53: 5523–5527.

    CAS  PubMed  Google Scholar 

  109. Lemoine NR, Staddon S, Bond J, Wyllie FS, Shaw JJ, WynfordThomas D. Partial transformation of human thyroid epithelial cells by mutant Ha-ras oncogene. Oncogene 1990; 5: 1833–1837.

    CAS  PubMed  Google Scholar 

  110. Jones CJ, Kipling D, Morris M, et al. Evidence for a telomereindependent “clock” limiting RAS oncogene-driven proliferation of human thyroid epithelial cells. Mol Cell Biol 2000; 20: 5690–5699.

    CAS  PubMed  Google Scholar 

  111. Fagin JA. Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid. Mol Endocrinol 2002; 16: 903–911.

    CAS  PubMed  Google Scholar 

  112. Saavedra HI, Knauf JA, Shirokawa JM, et al. The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. Oncogene 2000; 19: 3948–3954.

    CAS  PubMed  Google Scholar 

  113. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000; 289: 1357–1360.

    CAS  PubMed  Google Scholar 

  114. Mansouri A, Chowdhury K, Gruss P. Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 1998; 19: 87–90.

    CAS  PubMed  Google Scholar 

  115. Poleev A, Fickenscher H, Mundlos S, et al. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms’ tumors. Development 1992; 116: 611–623.

    CAS  PubMed  Google Scholar 

  116. Zannini M, Francis-Lang H, Plachov D, Di Lauro R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-speciifc promoters. Mol Cell Biol 1992; 12: 4230–4241.

    CAS  PubMed  Google Scholar 

  117. Ohno M, Zannini M, Levy O, Carrasco N, di Lauro R. The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription. Mol Cell Biol 1999; 19: 2051–2060.

    CAS  PubMed  Google Scholar 

  118. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999; 20: 649–688.

    CAS  PubMed  Google Scholar 

  119. Greene ME, Blumberg B, McBride OW, et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr 1995; 4: 281–299.

    CAS  PubMed  Google Scholar 

  120. Poleev A, Wendler F, Fickenscher H, et al. Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms’ tumors. Eur J Biochem 1995; 228: 899–911.

    CAS  PubMed  Google Scholar 

  121. Nikiforova MN, Caudill CM, Paul Biddinger PW, Kroll TG, Nikiforov YE. PAX8-PPARg rearrangement in thyroid tumors: RTPCR and immunohistochemical analyses. Am J Surg Pathol 2002; 26: 1016–1023.

    PubMed  Google Scholar 

  122. Roque L, Castedo S, Clode A, Soares J. Deletion of 3p25-) pter in a primary follicular thyroid carcinoma and its metastasis. Genes Chromosomes Cancer 1993; 8: 199–203.

    CAS  PubMed  Google Scholar 

  123. Shore RE. Issues and epidemiological evidence regarding radiation-induced thyroid cancer. Radiat Res 1992; 131: 98–111.

    CAS  PubMed  Google Scholar 

  124. Bartolazzi A, Gasbarri A, Papotti M, et al. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 2001; 357: 1644–1650.

    CAS  PubMed  Google Scholar 

  125. Ward LS, Brenta G, Medvedovic M, Fagin JA. Studies of allelic loss in thyroid tumors reveal major differences in chromosomal insta-bility between papillary and follicular carcinomas. J Clin Endocrinol Metab 1998; 83: 525–530.

    CAS  PubMed  Google Scholar 

  126. Kitamura Y, Shimizu K, Ito K, Tanaka S, Emi M. Allelotyping of follicular thyroid carcinoma: frequent allelic losses in chromosome arms 7q, 1 1p, and 22q. J Clin Endocrinol Metab 2001;86:4268– 4272.

    Google Scholar 

  127. Oriola J, Halperin I, Mallofre C, Muntane J, Angel M, Rivera-Fillat F. Screening of selected genomic areas potentially involved in thyroid neoplasms. Eur J Cancer 2001; 37: 2470–2474.

    CAS  PubMed  Google Scholar 

  128. Herrmann MA, Hay ID, Bartelt DH Jr, et al. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest 1991; 88: 1596–1604.

    CAS  PubMed  Google Scholar 

  129. Zedenius J, Wallin G, Svensson A, et al. Allelotyping of follicular thyroid tumors. Hum Genet 1995; 96: 27–32.

    CAS  PubMed  Google Scholar 

  130. Tung WS, Shevlin DW, Kaleem Z, Tribune DJ, Wells SA Jr, Goodfellow PJ. Allelotype of follicular thyroid carcinomas reveals genetic instability consistent with frequent nondisjunctional chromosomal loss. Genes Chromosomes Cancer 1997; 19: 43–51.

    CAS  PubMed  Google Scholar 

  131. Segev DL, Saji M, Phillips GS, et al. Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hurthle cell neoplasms of the thyroid. J Clin Endocrinol Metab 1998; 83: 2036–2042.

    CAS  PubMed  Google Scholar 

  132. Grebe SK, McIver B, Hay ID, et al. Frequent loss of heterozygosity on chromosomes 3p and 17p without VHL or p53 mutations suggests involvement of unidentified tumor suppressor genes in follicular thyroid carcinoma. J Clin Endocrinol Metab 1997; 82: 3684–3691.

    CAS  PubMed  Google Scholar 

  133. Erickson LA, Jalal SM, Goellner JR, et al. Analysis of Hurthle cell neoplasms of the thyroid by interphase fluorescence in situ hybridization. Am J Surg Pathol 2001; 25: 911–917.

    CAS  PubMed  Google Scholar 

  134. Mazzucchelli L, Burckhardt E, Hirsiger H, Kappeler A, Laissue JA. Interphase cytogenetics in oncocytic adenomas and carcinomas of the thyroid gland. Hum Pathol 2000; 31: 854–859.

    CAS  PubMed  Google Scholar 

  135. Schelfhout LJ, Cornelisse CJ, Goslings BM, et al. Frequency and degree of aneuploidy in benign and malignant thyroid neoplasms. Int J Cancer 1990; 45: 16–20.

    CAS  PubMed  Google Scholar 

  136. Jonasson JG, Hrafnkelsson J. Nuclear DNA analysis and prognosis in carcinoma of the thyroid gland. A nationwide study in Iceland on carcinomas diagnosed 1955–1990. Virchows Arch 1994; 425: 349–355.

    CAS  PubMed  Google Scholar 

  137. Joensuu H, Klemi P, Eerola E, Tuominen J. Influence of cellular DNA content on survival in differentiated thyroid cancer. Cancer 1986; 58: 2462–2467.

    CAS  PubMed  Google Scholar 

  138. Grant CS, Hay ID, Ryan JJ, Bergstralh EJ, Rainwater LM, Goellner JR. Diagnostic and prognostic utility of flow cytometric DNA measurements in follicular thyroid tumors. World J Surg 1990;14:283– 289; discussion 289–290.

    Google Scholar 

  139. Czyz W, Joensuu H, Pylkkanen L, Klemi PJ. p53 protein, PCNA staining, and DNA content in follicular neoplasms of the thyroid gland. J Pathol 1994; 174: 267–274.

    CAS  PubMed  Google Scholar 

  140. Oyama T, Vickery AL Jr, Preffer FI, Colvin RB. A comparative study of flow cytometry and histopathologic ifndings in thyroid follicular carcinomas and adenomas. Hum Pathol 1994; 25: 271–275.

    CAS  PubMed  Google Scholar 

  141. Nikiforov YE, Nikiforova M, Fagin JA. Prevalence of minisatellite and microsatellite instability in radiation-induced post-Chernobyl pediatric thyroid carcinomas. Oncogene 1998; 17: 1983–1988.

    CAS  PubMed  Google Scholar 

  142. Lazzereschi D, Palmirotta R, Ranieri A, et al. Microsatellite instability in thyroid tumours and tumour-like lesions. Br J Cancer 1999; 79: 340–345.

    CAS  PubMed  Google Scholar 

  143. Soares P, dos Santos NR, Seruca R, Lothe RA, Sobrinho-Simoes M. Benign and malignant thyroid lesions show instability at microsatellite loci. Eur J Cancer 1997; 33: 293–296.

    CAS  PubMed  Google Scholar 

  144. Armour JA, Patel I, Thein SL, Fey MF, Jeffreys AJ. Analysis of somatic mutations at human minisatellite loci in tumors and cell lines. Genomics 1989; 4: 328–334.

    CAS  PubMed  Google Scholar 

  145. Rousseau-Merck MF, Misrahi M, Loosfelt H, Atger M, Milgrom E, Berger R. Assignment of the human thyroid stimulating hormone receptor (TSHR) gene to chromosome 14q31. Genomics 1990; 8: 233–236.

    CAS  PubMed  Google Scholar 

  146. Gejman PV, Weinstein LS, Martinez M, et al. Genetic mapping of the Gs-alpha subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis. Genomics 1991; 9: 782–783.

    CAS  PubMed  Google Scholar 

  147. Krohn K, Fuhrer D, Holzapfel HP, Paschke R. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab 1998; 83: 130–134.

    CAS  PubMed  Google Scholar 

  148. Fuhrer D, Holzapfel HP, Wonerow P, Scherbaum WA, Paschke R. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 1997; 82: 3885–3891.

    CAS  PubMed  Google Scholar 

  149. Trulzsch B, Krohn K, Wonerow P, et al. Detection of thyroid-stimulating hormone receptor and Gs alpha mutations in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis. J Mol Med 2001; 78: 684–691.

    CAS  PubMed  Google Scholar 

  150. Parma J, Duprez L, Van Sande J, et al. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 1997; 82: 2695–2701.

    CAS  PubMed  Google Scholar 

  151. Krohn K, Paschke R. Clinical review 133: Progress in understanding the etiology of thyroid autonomy. J Clin Endocrinol Metab 2001; 86: 3336–3345.

    CAS  PubMed  Google Scholar 

  152. O’Sullivan C, Barton CM, Staddon SL, Brown CL, Lemoine NR. Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinogen 1991; 4: 345–349.

    Google Scholar 

  153. Esapa C, Foster S, Johnson S, Jameson JL, Kendall-Taylor P, Harris PE. G protein and thyrotropin receptor mutations in thyroid neoplasia. J Clin Endocrinol Metab 1997; 82: 493–496.

    CAS  PubMed  Google Scholar 

  154. Matsuo K, Friedman E, Gejman PV, Fagin JA. The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms. J Clin Endocrinol Metab 1993; 76: 1446–1451.

    CAS  PubMed  Google Scholar 

  155. Yen PM. Thyrotropin receptor mutations in thyroid diseases. Rev Endocr Metab Disord 2000; 1: 123–129.

    CAS  PubMed  Google Scholar 

  156. Ludgate M, Gire V, Crisp M, et al. Contrasting effects of activating mutations of GalphaS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells. Oncogene 1999; 18: 4798–4807.

    CAS  PubMed  Google Scholar 

  157. Michiels FM, Caillou B, Talbot M, et al. Oncogenic potential of guanine nucleotide stimulatory factor alpha subunit in thyroid glands of transgenic mice. Proc Natl Acad Sci USA 1994;91:10488– 10492.

    Google Scholar 

  158. Waite KA, Eng C. Protean PTEN: form and function. Am J Hum Genet 2002; 70: 829–844.

    CAS  PubMed  Google Scholar 

  159. Bruni P, Boccia A, Baldassarre G, et al. PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTENgrowth suppressing activity in thyroid cancer cells mediated by p27kip1. Oncogene 2000; 19: 3146–3155.

    CAS  PubMed  Google Scholar 

  160. Dahia PL, Marsh DJ, Zheng Z, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res 1997; 57: 4710–4713.

    CAS  PubMed  Google Scholar 

  161. Halachmi N, Halachmi S, Evron E, et al. Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors. Genes Chromosomes Cancer 1998; 23: 239–243.

    CAS  PubMed  Google Scholar 

  162. Gimm O, Perren A, Weng LP, et al. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am J Pathol 2000; 156: 1693–1700.

    CAS  PubMed  Google Scholar 

  163. Marsh DJ, Zheng Z, Zedenius J, et al. Differential loss of heterozygosity in the region of the Cowden locus within 10q22–23 in follicular thyroid adenomas and carcinomas. Cancer Res 1997; 57: 500–503.

    CAS  PubMed  Google Scholar 

  164. Gimm O, Chi H, Dahia PL, et al. Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas. J Clin Endocrinol Metab 2001; 86: 1801–1805.

    CAS  PubMed  Google Scholar 

  165. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol 2001; 11: 764–768.

    CAS  PubMed  Google Scholar 

  166. DeLellis RA. Multiple endocrine neoplasia syndromes revisited. Clinical, morphologic, and molecular features. Lab Invest 1995; 72: 494–505.

    CAS  PubMed  Google Scholar 

  167. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000; 88: 1139–1148.

    CAS  PubMed  Google Scholar 

  168. Mulligan LM, Marsh DJ, Robinson BG, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 1995; 238: 343–346.

    CAS  PubMed  Google Scholar 

  169. Eng C, Clayton D, Schuffenecker I, et al. The relationship between speciifc RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996; 276: 1575–1579.

    CAS  PubMed  Google Scholar 

  170. Hansford JR, Mulligan LM. Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet 2000; 37: 817–827.

    CAS  PubMed  Google Scholar 

  171. Eng C, Smith DP, Mulligan LM, et al. 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 1994; 3: 237–241.

    CAS  PubMed  Google Scholar 

  172. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367: 375–376.

    CAS  PubMed  Google Scholar 

  173. 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: 1613–1619.

    CAS  PubMed  Google Scholar 

  174. Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995; 267: 381–383.

    CAS  PubMed  Google Scholar 

  175. Songyang Z, Gish G, Mbamalu G, Pawson T, Cantley LC. A single point mutation switches the speciifcity of group III Src homology (SH) 2 domains to that of group I SH2 domains. J Biol Chem 1995; 270: 26029–26032.

    CAS  PubMed  Google Scholar 

  176. Borrello MG, Smith DP, Pasini B, et al. RET activation by germ-line MEN2A and MEN2B mutations. Oncogene 1995;11:2419– 2427.

    Google Scholar 

  177. Michiels FM, Chappuis S, Caillou B, et al. Development of medullary thyroid carcinoma in transgenic mice expressing the RET proto-oncogene altered by a multiple endocrine neoplasia type 2A mutation. Proc Natl Acad Sci USA 1997; 94: 3330–3335.

    CAS  PubMed  Google Scholar 

  178. Wells SA Jr, Skinner MA. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 1998; 106: 29–34.

    CAS  PubMed  Google Scholar 

  179. Niccoli-Sire P, Murat A, Baudin E, et al. Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol 1999; 141: 468–474.

    CAS  PubMed  Google Scholar 

  180. Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. Hum Mutat 1997; 9: 97–109.

    CAS  PubMed  Google Scholar 

  181. Kalinin VN, Amosenko FA, Shabanov MA, et al. Three novel mutations in the RET proto-oncogene. J Mol Med 2001;79:609– 612.

    Google Scholar 

  182. Asakawa H, Kobayashi T. Multistep carcinogenesis in anaplastic thyroid carcinoma: a case report. Pathology 2002; 34: 94–97.

    PubMed  Google Scholar 

  183. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 91: 179–184.

    CAS  PubMed  Google Scholar 

  184. Donghi R, Longoni A, Pilotti S, Michieli P, Della Porta G, Pierotti MA. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J Clin Invest 1993; 91: 1753–1760.

    CAS  PubMed  Google Scholar 

  185. Dobashi Y, Sugimura H, Sakamoto A, et al. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagn Mol Pathol 1994; 3: 9–14.

    CAS  PubMed  Google Scholar 

  186. Ho YS, Tseng SC, Chin TY, Hsieh LL, Lin JD. p53 gene mutation in thyroid carcinoma. Cancer Lett 1996; 103: 57–63.

    CAS  PubMed  Google Scholar 

  187. Takeuchi Y, Daa T, Kashima K, Yokoyama S, Nakayama I, Noguchi S. Mutations of p53 in thyroid carcinoma with an insular component. Thyroid 1999; 9: 377–381.

    CAS  PubMed  Google Scholar 

  188. Moretti F, Farsetti A, Soddu S, et al. p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells. Oncogene 1997; 14: 729–740.

    CAS  PubMed  Google Scholar 

  189. Fagin JA, Tang SH, Zeki K, Di Lauro R, Fusco A, Gonsky R. Reexpression of thyroid peroxidase in a derivative of an undifferentiated thyroid carcinoma cell line by introduction of wild-type p53. Cancer Res 1996; 56: 765–771.

    CAS  PubMed  Google Scholar 

  190. Kraus C, Liehr T, Hulsken J, et al. Localization of the human betacatenin gene (CTNNB 1) to 3p21: a region implicated in tumor development. Genomics 1994; 23: 272–274.

    CAS  PubMed  Google Scholar 

  191. van Hengel J, Nollet F, Berx G, van Roy N, Speleman F, van Roy F. Assignment of the human beta-catenin gene (CTNNB1) to 3p22-p21.3 by fluorescence in situ hybridization. Cytogenet Cell Genet 1995; 70: 68–70.

    PubMed  Google Scholar 

  192. Van Aken E, De Wever O, Correia da Rocha AS, Mareel M. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch 2001; 439: 725–751.

    PubMed  Google Scholar 

  193. Garcia-Rostan G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G. Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB 1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Am J Pathol 2001; 158: 987–996.

    CAS  PubMed  Google Scholar 

  194. Miyake N, Maeta H, Horie S, et al. Absence of mutations in the betacatenin and adenomatous polyposis coli genes in papillary and follicular thyroid carcinomas. Pathol Int 2001; 51: 680–685.

    CAS  PubMed  Google Scholar 

  195. Helmbrecht K, Kispert A, von Wasielewski R, Brabant G. Identification of a Wnt/beta-catenin signaling pathway in human thyroid cells. Endocrinology 2001; 142: 5261–5266.

    CAS  PubMed  Google Scholar 

  196. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8–PPARã rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003; 88: 2318–2326.

    CAS  PubMed  Google Scholar 

Download references

Authors
  1. Yuri E. Nikiforov MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pathology, Mayo Clinic, Rochester, MN, USA

    Ricardo V. Lloyd MD, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Nikiforov, Y.E. (2004). Recent Developments in the Molecular Biology of the Thyroid. In: Lloyd, R.V. (eds) Endocrine Pathology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-403-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-403-0_10

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-423-4

  • Online ISBN: 978-1-59259-403-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation