Table of Contents Author Guidelines Submit a Manuscript
Journal of Oncology
Volume 2010, Article ID 351679, 17 pages
http://dx.doi.org/10.1155/2010/351679
Review Article

Thyroid Cancer: Current Molecular Perspectives

Regional Centre for Hereditary Endocrine Tumors, Unit of Metabolic Bone Diseases, Department of Internal Medicine, University of Florence, Viale Morgagni 85, 50135 Florence, Italy

Received 30 December 2009; Accepted 21 January 2010

Academic Editor: Aysegula A. Sahin

Copyright © 2010 Francesca Giusti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. B. K. Edwards, M. L. Brown, P. A. Wingo et al., “Annual report to the nation on the status of cancer, 1975–2002, featuring population-based trends in cancer treatment,” Journal of the National Cancer Institute, vol. 97, no. 19, pp. 1407–1427, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Y. Chen, A. Jemal, and E. M. Ward, “Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005,” Cancer, vol. 115, no. 16, pp. 3801–3807, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. D. S. Cooper, G. M. Doherty, B. R. Haugen et al., “Management guidelines for patients with thyroid nodules and differentiated thyroid cancer,” Thyroid, vol. 16, no. 2, pp. 109–141, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. R. A. De Lellis, R. V. Lloyd, P. U. Heitz, and C. Eng, Eds., World Health Organization International Classification of Tumors. Pathology and Genetics of Tumors of Endocrine Organs, IARC Press, Lyon, France, 2004.
  5. I. D. Hay, “Papillary thyroid carcinoma,” Endocrinology and Metabolism Clinics of North America, vol. 19, no. 3, pp. 545–576, 1990. View at Google Scholar · View at Scopus
  6. D. S. Cooper and C. R. Schneyer, “Follicular and Hurthle cell carcinoma of the thyroid,” Endocrinology and Metabolism Clinics of North America, vol. 19, no. 3, pp. 577–591, 1990. View at Google Scholar · View at Scopus
  7. S. Chiacchio, A. Lorenzoni, G. Boni, D. Rubello, R. Elisei, and G. Mariani, “Anaplastic thyroid cancer: prevalence, diagnosis and treatment,” Minerva Endocrinologica, vol. 33, no. 4, pp. 341–357, 2008. View at Google Scholar · View at Scopus
  8. H. R. Harach, K. O. Franssila, and V.-M. Wasenius, “Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study,” Cancer, vol. 56, no. 3, pp. 531–538, 1985. View at Google Scholar · View at Scopus
  9. S. Franceschi, P. Boyle, P. Maisonneuve et al., “The epidemiology of thyroid carcinoma,” Critical Reviews in Oncogenesis, vol. 4, no. 1, pp. 25–52, 1993. View at Google Scholar · View at Scopus
  10. S. H. Landis, T. Murray, S. Bolden, and P. A. Wingo, “Cancer statistics,” CA: A Cancer Journal for Clinicians, vol. 48, no. 6, p. 329, 1998. View at Google Scholar
  11. A. Belfiore, G. L. La Rosa, G. A. La Porta et al., “Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity,” American Journal of Medicine, vol. 93, no. 4, pp. 363–369, 1992. View at Publisher · View at Google Scholar · View at Scopus
  12. D. M. Parkin, S. L. Whelan, J. Ferlay, J. Powell, and L. Teppo, Cancer Incidence in Five Continents, vol. 8 of IARC Scientific Publication no. 155, IARC Press, Lyon, France, 2003.
  13. G. A. Hanson, R. A. Komorowski, J. M. Cerletty, and S. D. Wilson, “Thyroid gland morphology in young adults: normal subjects versus those with prior low-dose neck irradiation in childhood,” Surgery, vol. 94, no. 6, pp. 984–988, 1983. View at Google Scholar · View at Scopus
  14. C.-H. Pui, C. Cheng, W. Leung et al., “Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia,” The New England Journal of Medicine, vol. 349, no. 7, pp. 640–649, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. S. L. Hancock, R. S. Cox, and I. R. McDougall, “Thyroid diseases after treatment of Hodgkin's disease,” The New England Journal of Medicine, vol. 325, no. 9, pp. 599–605, 1991. View at Google Scholar · View at Scopus
  16. E. Ron, J. H. Lubin, R. E. Shore et al., “Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies,” Radiation Research, vol. 141, no. 3, pp. 259–277, 1995. View at Publisher · View at Google Scholar · View at Scopus
  17. Y. Nikiforov and D. R. Gnepp, “Pediatric thyroid cancer after the Chernobyl disaster: pathomorphologic study of 84 cases (1991-1992) from the Republic of Belarus,” Cancer, vol. 74, no. 2, pp. 748–766, 1994. View at Google Scholar · View at Scopus
  18. L. Leenhardt and A. Aurengo, “Post-Chernobyl thyroid carcinoma in children,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 14, no. 4, pp. 667–677, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. L. M. Farbota, D. B. Calandra, A. M. Lawrence, and E. Paloyan, “Thyroid carcinoma in Graves' disease,” Surgery, vol. 98, no. 6, pp. 1148–1153, 1985. View at Google Scholar · View at Scopus
  20. F. Pacini, R. Elisei, G. C. Di Coscio et al., “Thyroid carcinoma in thyrotoxic patients treated by surgery,” Journal of Endocrinological Investigation, vol. 11, no. 2, pp. 107–112, 1988. View at Google Scholar · View at Scopus
  21. G. Pellegriti, A. Belfiore, D. Giuffrida, L. Lupo, and R. Vigneri, “Outcome of differentiated thyroid cancer in Graves' patients,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 8, pp. 2805–2809, 1998. View at Publisher · View at Google Scholar · View at Scopus
  22. K. Segal, M. Ben-Bassat, A. Avraham, G. Har-El, and J. Sidi, “Hashimoto's thyroiditis and carcinoma of the thyroid gland,” International Surgery, vol. 70, no. 3, pp. 205–209, 1985. View at Google Scholar · View at Scopus
  23. L. E. Holm, H. Blomgren, and T. Lowhagen, “Cancer risks in patients with chronic lymphocytic thyroiditis,” The New England Journal of Medicine, vol. 312, no. 10, pp. 601–604, 1985. View at Google Scholar · View at Scopus
  24. L. Dal Maso, C. L. Vecchia, S. Franceschi et al., “A pooled analysis of thyroid cancer studies. V. Anthropometric factors,” Cancer Causes and Control, vol. 11, no. 2, pp. 137–144, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. T. Suzuki, K. Matsuo, Y. Hasegawa et al., “Anthropometric factors at age 20 years and risk of thyroid cancer,” Cancer Causes and Control, vol. 19, no. 10, pp. 1233–1242, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. E. Negri, L. Dal Maso, E. Ron et al., “A pooled analysis of case-control studies of thyroid cancer. II. Menstrual and reproductive factors,” Cancer Causes and Control, vol. 10, no. 2, pp. 143–155, 1999. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Franceschi, S. Preston-Martin, L. Dal Maso et al., “A pooled analysis of case-control studies of thyroid cancer. IV. Benign thyroid diseases,” Cancer Causes and Control, vol. 10, no. 6, pp. 583–595, 1999. View at Google Scholar · View at Scopus
  28. M. T. Goodman, L. N. Kolonel, and L. R. Wilkens, “The association of body size, reproductive factors and thyroid cancer,” British Journal of Cancer, vol. 66, no. 6, pp. 1180–1184, 1992. View at Google Scholar · View at Scopus
  29. E. Ron, B. Lunenfeld, J. Menczer et al., “Cancer incidence in a cohort of infertile women,” American Journal of Epidemiology, vol. 125, no. 5, pp. 789–790, 1987. View at Google Scholar
  30. C. D. Malchoff and D. M. Malchoff, “Familial papillary thyroid carcinoma,” Cancer Treatment and Research, vol. 122, pp. 381–387, 2004. View at Google Scholar · View at Scopus
  31. V. A. Li Volsi, J. Albores-Saavedra, S. L. Asa et al., “Papillary carcinoma,” in Tumors of Endocrine Organs, R. A. DeLellis, R. V. Lloyd, P. U. Heitz, and C. Eng, Eds., World Health Organization Classification of Tumors, pp. 57–66, 2004. View at Google Scholar
  32. H. R. Harach, G. T. Williams, and E. D. Williams, “Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm,” Histopathology, vol. 25, no. 6, pp. 549–561, 1994. View at Google Scholar · View at Scopus
  33. R. Pilarski, “Cowden syndrome: a critical review of the clinical literature,” Journal of Genetic Counseling, vol. 18, no. 1, pp. 13–27, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. L. S. Kirschner, F. Sandrini, J. Monbo, J.-P. Lin, J. A. Carney, and C. A. Stratakis, “Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex,” Human Molecular Genetics, vol. 9, no. 20, pp. 3037–3046, 2000. View at Google Scholar · View at Scopus
  35. M. Casey, C. J. Vaughan, J. He et al., “Mutations in the protein kinase A R1a regulatory subunit cause familial cardiac myxomas and Carney complex,” Journal of Clinical Investigation, vol. 106, no. 5, pp. R31–R38, 2000. View at Google Scholar · View at Scopus
  36. J. Bertherat, A. Horvath, L. Groussin et al., “Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 6, pp. 2085–2091, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. F. Sandrini, L. Matyakhina, N. J. Sarlis et al., “Regulatory subunit type I-a of protein kinase A (PRKARIA): a tumor-suppressor gene for sporadic thyroid cancer,” Genes Chromosomes and Cancer, vol. 35, no. 2, pp. 182–192, 2002. View at Publisher · View at Google Scholar · View at Scopus
  38. L. S. Kirschner, D. F. Kusewitt, L. Matyakhina et al., “A mouse model for the carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues,” Cancer Research, vol. 65, no. 11, pp. 4506–4514, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. C. Peyssonnaux and A. Eychene, “The Raf/MEK/ERK pathway: new concepts of activation,” Biology of the Cell, vol. 93, no. 1-2, pp. 53–62, 2001. View at Publisher · View at Google Scholar · View at Scopus
  40. B. Dérijard, J. Raingeaud, T. Barrett et al., “Independent human MAP kinase signal transduction pathways defined by MEK and MKK isoforms,” Science, vol. 267, no. 5198, pp. 682–685, 1995. View at Google Scholar · View at Scopus
  41. G. Pearson, F. Robinson, T. Beers Gibson et al., “Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions,” Endocrine Reviews, vol. 22, no. 2, pp. 153–183, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. E. T. Kimura, M. N. Nikiforova, Z. Zhu, J. A. Knauf, Y. E. Nikiforov, and J. A. Fagin, “High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma,” Cancer Research, vol. 63, no. 7, pp. 1454–1457, 2003. View at Google Scholar · View at Scopus
  43. M. Xing, “BRAF mutation in thyroid cancer,” Endocrine-Related Cancer, vol. 12, no. 2, pp. 245–262, 2005. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. Cohen, M. Xing, E. Mambo et al., “BRAF mutation in papillary thyroid carcinoma,” Journal of the National Cancer Institute, vol. 95, no. 8, pp. 625–627, 2003. View at Google Scholar · View at Scopus
  45. M. Karasarides, A. Chiloeches, R. Hayward et al., “B-RAF is a therapeutic target in melanoma,” Oncogene, vol. 23, no. 37, pp. 6292–6298, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. P. T. C. Wan, M. J. Garnett, S. M. Roe et al., “Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF,” Cell, vol. 116, no. 6, pp. 855–867, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. A. J. Adeniran, Z. Zhu, M. Gandhi et al., “Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas,” American Journal of Surgical Pathology, vol. 30, no. 2, pp. 216–222, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. V. Trovisco, I. Vieira de Castro, P. Soares et al., “BRAF mutations are associated with some histological types of papillary thyroid carcinoma,” Journal of Pathology, vol. 202, no. 2, pp. 247–251, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. C. Carta, S. Moretti, L. Passeri et al., “Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAFV599Ins),” Clinical Endocrinology, vol. 64, no. 1, pp. 105–109, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. P. Hou, D. Liu, and M. Xing, “Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer,” Cell Cycle, vol. 6, no. 3, pp. 377–379, 2007. View at Google Scholar · View at Scopus
  51. R. Ciampi, J. A. Knauf, R. Kerler et al., “Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer,” Journal of Clinical Investigation, vol. 115, no. 1, pp. 94–101, 2005. View at Publisher · View at Google Scholar · View at Scopus
  52. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10142.
  53. M. N. Nikiforova, E. T. Kimura, M. Gandhi et al., “BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 11, pp. 5399–5404, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Namba, M. Nakashima, T. Hayashi et al., “Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 9, pp. 4393–4397, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Xing, W. H. Westra, R. P. Tufano et al., “BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 12, pp. 6373–6379, 2005. View at Publisher · View at Google Scholar · View at Scopus
  56. L. Fugazzola, D. Mannavola, V. Cirello et al., “BRAF mutations in an Italian cohort of thyroid cancers,” Clinical Endocrinology, vol. 61, no. 2, pp. 239–243, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. V. Trovisco, P. Soares, A. Preto et al., “Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness,” Virchows Archiv, vol. 446, no. 6, pp. 589–595, 2005. View at Publisher · View at Google Scholar · View at Scopus
  58. T. Y. Kim, W. B. Kim, Y. S. Rhee et al., “The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma,” Clinical Endocrinology, vol. 65, no. 3, pp. 364–368, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. G. Riesco-Eizaguirre, P. Gutiérrez-Martínez, M. A. García-Cabezas, M. Nistal, and P. Santisteban, “The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I targeting to the membrane,” Endocrine-Related Cancer, vol. 13, no. 1, pp. 257–269, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Begum, E. Rosenbaum, R. Henrique, Y. Cohen, D. Sidransky, and W. H. Westra, “BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment,” Modern Pathology, vol. 17, no. 11, pp. 1359–1363, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. J. A. Knauf, X. Ma, E. P. Smith et al., “Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation,” Cancer Research, vol. 65, no. 10, pp. 4238–4245, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. R.-T. Liu, C.-Y. Hou, H.-L. You et al., “Selective occurrence of RAS mutations in benign and malignant thyroid follicular neoplasms in Taiwan,” Thyroid, vol. 14, no. 8, pp. 616–621, 2004. View at Publisher · View at Google Scholar · View at Scopus
  63. H. Namba, S. A. Rubin, and J. A. Fagin, “Point mutations of RAS oncogenes are an early event in thyroid tumorigenesis,” Molecular Endocrinology, vol. 4, no. 10, pp. 1474–1479, 1990. View at Google Scholar · View at Scopus
  64. S. Ezzat, L. Zheng, J. Kolenda, A. Safarian, J. L. Freeman, and S. L. Asa, “Prevalence of activating RAS mutations in morphologically characterized thyroid nodules,” Thyroid, vol. 6, no. 5, pp. 409–416, 1996. View at Google Scholar · View at Scopus
  65. V. V. Vasko, J. Gaudart, C. Allasia et al., “Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma,” European Journal of Endocrinology, vol. 151, no. 6, pp. 779–786, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. N. R. Lemoine, E. S. Mayall, F. S. Wyllie et al., “High frequency of RAS oncogene activation in all stages of human thyroid tumorigenesis,” Oncogene, vol. 4, no. 2, pp. 159–164, 1989. View at Google Scholar · View at Scopus
  67. H. G. Suarez, J. A. du Villard, M. Severino et al., “Presence of mutations in all three RAS genes in human thyroid tumors,” Oncogene, vol. 5, no. 4, pp. 565–570, 1990. View at Google Scholar · View at Scopus
  68. C. T. Esapa, S. J. Johnson, P. Kendall-Taylor, T. W. J. Lennard, and P. E. Harris, “Prevalence of RAS mutations in thyroid neoplasia,” Clinical Endocrinology, vol. 50, no. 4, pp. 529–535, 1999. View at Publisher · View at Google Scholar · View at Scopus
  69. N. Motoi, A. Sakamoto, T. Yamochi, H. Horiuchi, T. Motoi, and R. Machinami, “Role of RAS mutation in the progression of thyroid carcinoma of follicular epithelial origin,” Pathology Research and Practice, vol. 196, no. 1, pp. 1–7, 2000. View at Google Scholar · View at Scopus
  70. F. Basolo, F. Pisaturo, L. E. Pollina et al., “N-RAS mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression,” Thyroid, vol. 10, no. 1, pp. 19–23, 2000. View at Google Scholar · View at Scopus
  71. C. Schark, N. Fulton, R. F. Jacoby, C. A. Westbrook, F. H. Straus II, and E. L. Kaplan, “N-RAS 61 oncogene mutations in Hurthle cell tumors,” Surgery, vol. 108, no. 6, pp. 994–1000, 1990. View at Google Scholar · View at Scopus
  72. G. Tallini, A. Hsueh, S. Liu, G. Garcia-Rostan, M. R. Speicher, and D. C. Ward, “Frequent chromosomal DNA unbalance in thyroid oncocytic (Hurthle cell) neoplasms detected by comparative genomic hybridization,” Laboratory Investigation, vol. 79, no. 5, pp. 547–555, 1999. View at Google Scholar · View at Scopus
  73. H. Asakawa and T. Kobayashi, “Multistep carcinogenesis in anaplastic thyroid carcinoma: a case report,” Pathology, vol. 34, no. 1, pp. 94–97, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. A. J. Adeniran, Z. Zhu, M. Gandhi et al., “Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas,” American Journal of Surgical Pathology, vol. 30, no. 2, pp. 216–222, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. Z. Zhu, M. Gandhi, M. N. Nikiforova, A. H. Fischer, and Y. E. Nikiforov, “Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma: an unusually high prevalence of RAS mutations,” American Journal of Clinical Pathology, vol. 120, no. 1, pp. 71–77, 2003. View at Publisher · View at Google Scholar · View at Scopus
  76. H. Hara, N. Fulton, T. Yashiro et al., “N-RAS mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma,” Surgery, vol. 116, no. 6, pp. 1010–1016, 1994. View at Google Scholar · View at Scopus
  77. G. Garcia-Rostan, H. Zhao, R. L. Camp et al., “RAS mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer,” Journal of Clinical Oncology, vol. 21, no. 17, pp. 3226–3235, 2003. View at Publisher · View at Google Scholar · View at Scopus
  78. H. Karga, J.-K. Lee, A. L. Vickery Jr., A. Thor, R. D. Gaz, and J. L. Jameson, “RAS oncogene mutations in benign and malignant thyroid neoplasms,” Journal of Clinical Endocrinology and Metabolism, vol. 73, no. 4, pp. 832–836, 1991. View at Google Scholar · View at Scopus
  79. G. Manenti, S. Pilotti, F. C. Re, G. Della Porta, and M. A. Pierotti, “Selective activation of RAS oncogenes in follicular and undifferentiated thyroid carcinomas,” European Journal of Cancer A, vol. 30, no. 7, pp. 987–993, 1994. View at Publisher · View at Google Scholar · View at Scopus
  80. J. A. Fagin, “Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid,” Molecular Endocrinology, vol. 16, no. 5, pp. 903–911, 2002. View at Publisher · View at Google Scholar · View at Scopus
  81. H. I. Saavedra, J. A. Knauf, J. M. Shirokawa et al., “The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway,” Oncogene, vol. 19, no. 34, pp. 3948–3954, 2000. View at Google Scholar · View at Scopus
  82. M. Takahashi, Y. Buma, T. Iwamoto, Y. Inaguma, H. Ikeda, and H. Hiai, “Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains,” Oncogene, vol. 3, no. 5, pp. 571–578, 1988. View at Google Scholar · View at Scopus
  83. K. Robertson and I. Mason, “The GDNF-KET signalling partnership,” Trends in Genetics, vol. 13, no. 1, pp. 1–3, 1997. View at Google Scholar · View at Scopus
  84. C. J. Marshall, “Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation,” Cell, vol. 80, no. 2, pp. 179–185, 1995. View at Google Scholar · View at Scopus
  85. G. Tallini, M. Santoro, M. Helie et al., “RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes,” Clinical Cancer Research, vol. 4, no. 2, pp. 287–294, 1998. View at Google Scholar · View at Scopus
  86. R. F. Gagel and S. J. Marx, “Multiple endocrine neoplasia,” in Book Multiple Endocrine Neoplasia, P. R. Larsen, H. Kronenberg, S. Melmed, and K. S. Polonsky, Eds., pp. 1762–1771, W. B. Saunders, Philadelphia, Pa, USA, 10th edition, 2003. View at Google Scholar
  87. M. L. Brandi, R. F. Gagel, A. Angeli et al., “Consensus: guidelines for diagnosis and therapy of MEN type 1 and type 2,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 12, pp. 5658–5671, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. L. M. Mulligan, D. J. Marsh, B. G. Robinson et al., “Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium,” Journal of Internal Medicine, vol. 238, no. 4, pp. 343–346, 1995. View at Google Scholar · View at Scopus
  89. M. Santoro, R. M. Melillo, F. Carlomagno et al., “Molecular biology of the MEN2 gene,” Journal of Internal Medicine, vol. 243, no. 6, pp. 505–508, 1998. View at Publisher · View at Google Scholar · View at Scopus
  90. J. R. Hansford and L. M. Mulligan, “Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis,” Journal of Medical Genetics, vol. 37, no. 11, pp. 817–827, 2000. View at Google Scholar · View at Scopus
  91. C. Eng, L. M. Mulligan, D. P. Smith et al., “Low frequency of germline mutations in the RET protooncogene in patients with apparently sporadic medullary thyroid carcinoma,” Clinical Endocrinology, vol. 43, no. 1, pp. 123–127, 1995. View at Google Scholar · View at Scopus
  92. R. A. Decker, M. L. Peacock, M. J. Borst et al., “Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete?” Surgery, vol. 118, no. 2, pp. 257–264, 1995. View at Publisher · View at Google Scholar · View at Scopus
  93. Y. Kitamura, P. J. Goodfellow, K. Shimizu et al., “Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC,” Oncogene, vol. 14, no. 25, pp. 3103–3106, 1997. View at Publisher · View at Google Scholar · View at Scopus
  94. C. J. M. Lips, “Clinical management of the multiple endocrine neoplasia syndromes: results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau Disease,” Journal of Internal Medicine, vol. 243, no. 6, pp. 589–594, 1998. View at Publisher · View at Google Scholar · View at Scopus
  95. C. Eng, L. M. Mulligan, C. S. Healey et al., “Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma,” Cancer Research, vol. 56, no. 9, pp. 2167–2170, 1996. View at Google Scholar · View at Scopus
  96. L. Alberti, C. Carniti, C. Miranda, E. Roccato, and M. A. Pierotti, “RET and NTRK1 proto-oncogenes in human diseases,” Journal of Cellular Physiology, vol. 195, no. 2, pp. 168–186, 2003. View at Publisher · View at Google Scholar · View at Scopus
  97. K. Frank-Raue, A. Machens, C. Scheuba, B. Niederle, H. Dralle, and F. Raue, “Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791,” Clinical Endocrinology, vol. 69, no. 2, pp. 259–263, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. M. Wiench, Z. Wygoda, E. Gubala et al., “Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients,” Journal of Clinical Oncology, vol. 19, no. 5, pp. 1374–1380, 2001. View at Google Scholar · View at Scopus
  99. H. Vierhapper, C. Bieglmayer, G. Heinze, and S. Baumgartner-Parzer, “Frequency of RET proto-oncogene mutations in patients with normal and with moderately elevated pentagastrin-stimulated serum concentrations of calcitonin,” Thyroid, vol. 14, no. 8, pp. 580–583, 2004. View at Publisher · View at Google Scholar · View at Scopus
  100. A. Machens, P. Niccoli-Sire, J. Hoegel et al., “Early malignant progression of hereditary medullary thyroid cancer,” The New England Journal of Medicine, vol. 349, no. 16, pp. 1517–1525, 2003. View at Publisher · View at Google Scholar · View at Scopus
  101. M. Colombo-Benkmann, Z. Li, B. Riemann et al., “Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma,” European Journal of Endocrinology, vol. 158, no. 6, pp. 811–816, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Greco, E. Roccato, and M. A. Pierotti, “TRK oncogenes in papillary thyroid carcinoma,” Cancer Treatment and Research, vol. 122, pp. 207–219, 2004. View at Google Scholar · View at Scopus
  103. I. Bongarzone, P. Vigneri, L. Mariani, P. Collini, S. Pilotti, and M. A. Pierotti, “RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features,” Clinical Cancer Research, vol. 4, no. 1, pp. 223–228, 1998. View at Google Scholar · View at Scopus
  104. L. C. Cantley and B. G. Neel, “New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 8, pp. 4240–4245, 1999. View at Publisher · View at Google Scholar · View at Scopus
  105. G. García-Rostán, A. M. Costa, I. Pereira-Castro et al., “Mutation of the PIK3CA gene in anaplastic thyroid cancer,” Cancer Research, vol. 65, no. 22, pp. 10199–10207, 2005. View at Publisher · View at Google Scholar · View at Scopus
  106. P. Hou, D. Liu, Y. Shan et al., “Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer,” Clinical Cancer Research, vol. 13, no. 4, pp. 1161–1170, 2007. View at Publisher · View at Google Scholar · View at Scopus
  107. Y. Wang, P. Hou, H. Yu et al., “High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/Akt pathway in thyroid tumors,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, pp. 2387–2390, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. P. L. M. Dahia, D. J. Marsh, Z. Zheng et al., “Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors,” Cancer Research, vol. 57, no. 21, pp. 4710–4713, 1997. View at Google Scholar · View at Scopus
  109. F. Moretti, A. Farsetti, S. Soddu et al., “p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells,” Oncogene, vol. 14, no. 6, pp. 729–740, 1997. View at Google Scholar · View at Scopus
  110. J. A. Fagin, S.-H. Tang, K. Zeki, R. Di Lauro, A. Fusco, and R. Gonsky, “Reexpression of thyroid peroxidase in a derivative of an undifferentiated thyroid carcinoma cell line by introduction of wild-type p53,” Cancer Research, vol. 56, no. 4, pp. 765–771, 1996. View at Google Scholar · View at Scopus
  111. J. A. Fagin, K. Matsuo, A. Karmakar, D. L. Chen, S.-H. Tang, and H. P. Koeffler, “High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas,” Journal of Clinical Investigation, vol. 91, no. 1, pp. 179–184, 1993. View at Google Scholar · View at Scopus
  112. R. Donghi, A. Longoni, S. Pilotti, P. Michieli, G. Della Porta, and M. A. Pierotti, “Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland,” Journal of Clinical Investigation, vol. 91, no. 4, pp. 1753–1760, 1993. View at Google Scholar · View at Scopus
  113. Y. Dobashi, H. Sugimura, A. Sakamoto et al., “Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas,” Diagnostic Molecular Pathology, vol. 3, no. 1, pp. 9–14, 1994. View at Google Scholar · View at Scopus
  114. Y.-S. Ho, S.-C. Tseng, T.-Y. Chin, L.-L. Hsieh, and J.-D. Lin, “p53 gene mutation in thyroid carcinoma,” Cancer Letters, vol. 103, no. 1, pp. 57–63, 1996. View at Publisher · View at Google Scholar · View at Scopus
  115. Y. Takeuchi, T. Daa, K. Kashima, S. Yokoyama, I. Nakayama, and S. Noguchi, “Mutations of p53 in thyroid carcinoma with an insular component,” Thyroid, vol. 9, no. 4, pp. 377–381, 1999. View at Google Scholar · View at Scopus
  116. C. Kraus, T. Liehr, J. Hülsken et al., “Localization of the human ß-catenin gene (CTNNB1) to 3p21: a region implicated in tumor development,” Genomics, vol. 23, no. 1, pp. 272–274, 1994. View at Publisher · View at Google Scholar · View at Scopus
  117. J. Van Hengel, F. Nollet, G. Berx, N. van Roy, F. Speleman, and F. van Roy, “Assignment of the human β-catenin gene (CTNNB1) to 3p22p21.3 by fluorescence in situ hybridization,” Cytogenetics and Cell Genetics, vol. 70, no. 1-2, pp. 68–70, 1995. View at Google Scholar · View at Scopus
  118. D.-C. Lie, S. A. Colamarino, H.-J. Song et al., “Wnt signalling regulates adult hippocampal neurogenesis,” Nature, vol. 437, no. 7063, pp. 1370–1375, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. G. Garcia-Rostan, R. L. Camp, A. Herrero, M. L. Carcangiu, D. L. Rimm, and G. Tallini, “β-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis,” American Journal of Pathology, vol. 158, no. 3, pp. 987–996, 2001. View at Google Scholar · View at Scopus
  120. N. Miyake, H. Maeta, S. Horie et al., “Absence of mutations in the ß-catenin and adenomatous polyposis coli genes in papillary and follicular thyroid carcinomas,” Pathology International, vol. 51, no. 9, pp. 680–685, 2001. View at Publisher · View at Google Scholar · View at Scopus
  121. V. Máximo, P. Soares, J. Lima, J. Cameselle-Teijeiro, and M. Sobrinho-Simões, “Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hurthle cell tumors,” American Journal of Pathology, vol. 160, no. 5, pp. 1857–1865, 2002. View at Google Scholar · View at Scopus
  122. V. Máximo, T. Botelho, J. Capela et al., “Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid,” British Journal of Cancer, vol. 92, no. 10, pp. 1892–1898, 2005. View at Publisher · View at Google Scholar · View at Scopus
  123. M. Grieco, M. Santoro, M. T. Berlingieri 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, vol. 60, no. 4, pp. 557–563, 1990. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Santoro, N. A. Dathan, M. T. Berlingieri et al., “Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma,” Oncogene, vol. 9, no. 2, pp. 509–516, 1994. View at Google Scholar · View at Scopus
  125. I. Bongarzone, N. Monzini, M. G. Borrello et al., “Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RIa of cyclic AMP-dependent protein kinase A,” Molecular and Cellular Biology, vol. 13, no. 1, pp. 358–366, 1993. View at Google Scholar · View at Scopus
  126. L. Fugazzola, M. A. Pierotti, E. Vigano, F. Pacini, T. V. Vorontsova, and I. Bongarzone, “Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer,” Oncogene, vol. 13, no. 5, pp. 1093–1097, 1996. View at Google Scholar · View at Scopus
  127. Y. E. Nikiforov, J. M. Rowland, K. E. Bove, H. Monforte-Munoz, and J. A. Fagin, “Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children,” Cancer Research, vol. 57, no. 9, pp. 1690–1694, 1997. View at Google Scholar · View at Scopus
  128. P. Soares, E. Fonseca, D. Wynford-Thomas, and M. Sobrinho-Simões, “Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms?” Journal of Pathology, vol. 185, no. 1, pp. 71–78, 1998. View at Google Scholar · View at Scopus
  129. H. M. Rabes, E. P. Demidchik, J. D. Sidorow et al., “Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications,” Clinical Cancer Research, vol. 6, no. 3, pp. 1093–1103, 2000. View at Google Scholar · View at Scopus
  130. C. L. Fenton, Y. Lukes, D. Nicholson, C. A. Dinauer, G. L. Francis, and R. M. Tuttle, “The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 3, pp. 1170–1175, 2000. View at Publisher · View at Google Scholar · View at Scopus
  131. T. Nakata, Y. Kitamura, K. Shimizu et al., “Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma,” Genes Chromosomes and Cancer, vol. 25, no. 2, pp. 97–103, 1999. View at Google Scholar · View at Scopus
  132. R. Ciampi, T. J. Giordano, K. Wikenheiser-Brokamp, R. J. Koenig, and Y. E. Nikiforov, “HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma,” Endocrine-Related Cancer, vol. 14, no. 2, pp. 445–452, 2007. View at Publisher · View at Google Scholar · View at Scopus
  133. J. A. Knauf, H. Kuroda, S. Basu, and J. A. Fagin, “RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase,” Oncogene, vol. 22, no. 28, pp. 4406–4412, 2003. View at Publisher · View at Google Scholar · View at Scopus
  134. K. S. Ravichandran, “Signaling via Shc family adapter proteins,” Oncogene, vol. 20, no. 44, pp. 6322–6330, 2001. View at Publisher · View at Google Scholar · View at Scopus
  135. G. Tallini and S. L. Asa, “RET oncogene activation in papillary thyroid carcinoma,” Advances in Anatomic Pathology, vol. 8, no. 6, pp. 345–354, 2001. View at Google Scholar · View at Scopus
  136. Y. E. Nikiforov, “RET/PTC rearrangement in thyroid tumors,” Endocrine Pathology, vol. 13, no. 1, pp. 3–16, 2002. View at Google Scholar · View at Scopus
  137. G. Viglietto, G. Chiappetta, F. J. Martinez-Tello et al., “RET/PTC oncogene activation is an early event in thyroid carcinogenesis,” Oncogene, vol. 11, no. 6, pp. 1207–1210, 1995. View at Google Scholar · View at Scopus
  138. O. M. Sheils, J. J. O'Eary, V. Uhlmann, K. Luttich, and E. C. Sweeney, “ret/PTC-1 activation in Hashimoto thyroiditis,” International Journal of Surgical Pathology, vol. 8, no. 3, pp. 185–189, 2000. View at Google Scholar · View at Scopus
  139. R. Elisei, C. Romei, T. Vorontsova et al., “RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 7, pp. 3211–3216, 2001. View at Publisher · View at Google Scholar · View at Scopus
  140. C. C. Cheung, B. Carydis, S. Ezzat, Y. C. Bedard, and S. L. Asa, “Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 5, pp. 2187–2190, 2001. View at Publisher · View at Google Scholar · View at Scopus
  141. T. G. Kroll, P. Sarraf, L. Pecciarini et al., “PAX8-PPAR?1 fusion in oncogene human thyroid carcinoma,” Science, vol. 289, no. 5483, pp. 1357–1360, 2000. View at Publisher · View at Google Scholar · View at Scopus
  142. C. A. French, E. K. Alexander, E. S. Cibas et al., “Genetic and biological subgroups of low-stage follicular thyroid cancer,” American Journal of Pathology, vol. 162, no. 4, pp. 1053–1060, 2003. View at Google Scholar · View at Scopus
  143. M. N. Nikiforova, R. A. Lynch, P. W. Biddinger et al., “RAS point mutations and PAX8-PPAR? rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 5, pp. 2318–2326, 2003. View at Publisher · View at Google Scholar · View at Scopus
  144. T. Dwight, S. R. Thoppe, T. Foukakis et al., “Involvement of the PAX8/peroxisome proliferator-activated receptor ? rearrangement in follicular thyroid tumors,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 9, pp. 4440–4445, 2003. View at Publisher · View at Google Scholar · View at Scopus
  145. A. R. Marques, C. Espadinha, A. L. Catarino et al., “Expression of PAX8-PPAR?1 rearrangements in both follicular thyroid carcinomas and adenomas,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 8, pp. 3947–3952, 2002. View at Publisher · View at Google Scholar · View at Scopus
  146. M. N. Nikiforova, P. W. Biddinger, C. M. Caudill, T. G. Kroll, and Y. E. Nikiforov, “PAX8-PPARγ rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses,” American Journal of Surgical Pathology, vol. 26, no. 8, pp. 1016–1023, 2002. View at Publisher · View at Google Scholar · View at Scopus
  147. J. Gregory Powell, X. Wang, B. L. Allard et al., “The PAX8/PPAR? fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPAR? inhibition,” Oncogene, vol. 23, no. 20, pp. 3634–3641, 2004. View at Publisher · View at Google Scholar · View at Scopus
  148. T. J. Giordano, A. Y. M. Au, R. Kuick et al., “Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation,” Clinical Cancer Research, vol. 12, no. 7, pp. 1983–1993, 2006. View at Publisher · View at Google Scholar · View at Scopus
  149. H. V. Reddi, B. McIver, S. K. G. Grebe, and N. L. Eberhardt, “Minireview: the paired box-8/peroxisome proliferator-activated receptor-γ oncogene in thyroid tumorigenesis,” Endocrinology, vol. 148, no. 3, pp. 932–935, 2007. View at Publisher · View at Google Scholar · View at Scopus
  150. L. S. Ward, G. Brenta, M. Medvedovic, and J. A. Fagin, “Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 2, pp. 525–530, 1998. View at Publisher · View at Google Scholar · View at Scopus
  151. J. L. Hunt, V. A. Livolsi, Z. W. Baloch et al., “A novel microdissection and genotyping of follicular-derived thyroid tumors to predict aggressiveness,” Human Pathology, vol. 34, no. 4, pp. 375–380, 2003. View at Publisher · View at Google Scholar · View at Scopus
  152. A. Rodrigues-Serpa, A. Catarino, and J. Soares, “Loss of heterozygosity in follicular and papillary thyroid carcinomas,” Cancer Genetics and Cytogenetics, vol. 141, no. 1, pp. 26–31, 2003. View at Publisher · View at Google Scholar · View at Scopus
  153. J. L. Hunt, J. H. Yim, and S. E. Carty, “Fractional allelic loss of tumor suppressor genes identifies malignancy and predicts clinical outcome in follicular thyroid tumors,” Thyroid, vol. 16, no. 7, pp. 643–649, 2006. View at Publisher · View at Google Scholar · View at Scopus
  154. J. Zedenius, G. Wallin, A. Svensson et al., “Allelotyping of follicular thyroid tumors,” Human Genetics, vol. 96, no. 1, pp. 27–32, 1995. View at Publisher · View at Google Scholar · View at Scopus
  155. W. S. Tung, D. W. Shevlin, Z. Kaleem, D. J. Tribune, S. A. Wells Jr., and P. J. Goodfellow, “Allelotype of follicular thyroid carcinomas reveals genetic instability consistent with frequent nondisjunctional chromosomal loss,” Genes Chromosomes and Cancer, vol. 19, no. 1, pp. 43–51, 1997. View at Google Scholar · View at Scopus
  156. D. L. Segev, M. Saji, G. S. Phillips et al., “Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hurthle cell neoplasms of the thyroid,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 6, pp. 2036–2042, 1998. View at Publisher · View at Google Scholar · View at Scopus
  157. J. L. Hunt, J. H. Yim, M. Tometsko et al., “Loss of heterozygosity of the VHL gene identifies malignancy and predicts death in follicular thyroid tumors,” Surgery, vol. 134, no. 6, pp. 1043–1048, 2003. View at Publisher · View at Google Scholar · View at Scopus
  158. A. Israel, R. Sharan, E. Ruppin, and E. Galun, “Increased MicroRNA activity in human cancers,” PLoS One, vol. 4, no. 6, article e6045, 2009. View at Publisher · View at Google Scholar · View at Scopus
  159. K. Jazdzewski, S. Liyanarachchi, M. Swierniak et al., “Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 5, pp. 1502–1505, 2009. View at Publisher · View at Google Scholar · View at Scopus
  160. P. Pallante, R. Visone, M. Ferracin et al., “MicroRNA deregulation in human thyroid papillary carcinomas,” Endocrine-Related Cancer, vol. 13, no. 2, pp. 497–508, 2006. View at Publisher · View at Google Scholar · View at Scopus
  161. H. J. Kim, Y. H. Kim, D. S. Lee, J.-K. Chung, and S. Kim, “In vivo imaging of functional targeting of miR-221 in papillary thyroid carcinoma,” Journal of Nuclear Medicine, vol. 49, no. 10, pp. 1686–1693, 2008. View at Publisher · View at Google Scholar · View at Scopus
  162. M. N. Nikiforova, S. I. Chiosea, and Y. E. Nikiforov, “MicroRNA expression profiles in thyroid tumors,” Endocrine Pathology, vol. 20, no. 2, pp. 85–91, 2009. View at Publisher · View at Google Scholar · View at Scopus
  163. C. K. Galang and C. A. Hauser, “Cooperative DNA binding of the highly conserved human Hox 2.1 homeodomain gene product,” The New Biologist, vol. 4, no. 5, pp. 558–568, 1992. View at Google Scholar · View at Scopus
  164. J. F. Lyons, S. Wilhelm, B. Hibner, and G. Bollag, “Discovery of a novel Raf kinase inhibitor,” Endocrine-Related Cancer, vol. 8, no. 3, pp. 219–225, 2001. View at Publisher · View at Google Scholar · View at Scopus
  165. S. M. Wilhelm, C. Carter, L. Tang et al., “BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis,” Cancer Research, vol. 64, no. 19, pp. 7099–7109, 2004. View at Publisher · View at Google Scholar · View at Scopus
  166. P. T. C. Wan, M. J. Garnett, S. M. Roe et al., “Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF,” Cell, vol. 116, no. 6, pp. 855–867, 2004. View at Publisher · View at Google Scholar · View at Scopus
  167. E. Baudin and M. Schlumberger, “New therapeutic approaches for metastatic thyroid carcinoma,” Lancet Oncology, vol. 8, no. 2, pp. 148–156, 2007. View at Publisher · View at Google Scholar · View at Scopus
  168. B. Ouyang, J. A. Knauf, E. P. Smith et al., “Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo,” Clinical Cancer Research, vol. 12, no. 6, pp. 1785–1793, 2006. View at Publisher · View at Google Scholar · View at Scopus
  169. Y. Kodama, N. Asai, K. Kawai et al., “The RET proto-oncogene: a molecular therapeutic target in thyroid cancer,” Cancer Science, vol. 96, no. 3, pp. 143–148, 2005. View at Publisher · View at Google Scholar · View at Scopus
  170. M. Taniguchi, Y. Uehara, M. Matsuyama, and M. Takahashi, “Inhibition of ret tyrosine kinase activity by herbimycin A,” Biochemical and Biophysical Research Communications, vol. 195, no. 1, pp. 208–214, 1993. View at Publisher · View at Google Scholar · View at Scopus
  171. G. Cassinelli, C. Lanzi, T. Pensa et al., “Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin,” Biochemical Pharmacology, vol. 59, no. 12, pp. 1539–1547, 2000. View at Publisher · View at Google Scholar · View at Scopus
  172. C. J. Strock, J.-I. Park, M. Rosen et al., “CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth,” Cancer Research, vol. 63, no. 17, pp. 5559–5563, 2003. View at Google Scholar · View at Scopus
  173. F. Carlomagno, D. Vitagliano, T. Guida et al., “The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes,” Cancer Research, vol. 62, no. 4, pp. 1077–1082, 2002. View at Google Scholar · View at Scopus
  174. F. Carlomagno, D. Vitagliano, T. Guida et al., “Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2),” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 4, pp. 1897–1902, 2003. View at Publisher · View at Google Scholar · View at Scopus
  175. F. Carlomagno, D. Vitagliano, T. Guida et al., “ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases,” Cancer Research, vol. 62, no. 24, pp. 7284–7290, 2002. View at Google Scholar · View at Scopus
  176. M. Vidal, S. Wells, A. Ryan, and R. Cagan, “ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma,” Cancer Research, vol. 65, no. 9, pp. 3538–3541, 2005. View at Publisher · View at Google Scholar · View at Scopus
  177. C. Lanzi, G. Cassinelli, T. Pensa et al., “Inhibition of transforming activity of the Ret/Ptc1 oncoprotein by a 2-indolinone derivative,” International Journal of Cancer, vol. 85, no. 3, pp. 384–390, 2000. View at Google Scholar · View at Scopus
  178. C. Lanzi, G. Cassinelli, G. Cuccuru et al., “Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1,” Cellular and Molecular Life Sciences, vol. 60, no. 7, pp. 1449–1459, 2003. View at Publisher · View at Google Scholar · View at Scopus
  179. G. Cuccuru, C. Lanzi, G. Cassinelli et al., “Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma,” Journal of the National Cancer Institute, vol. 96, no. 13, pp. 1006–1014, 2004. View at Google Scholar · View at Scopus
  180. S. R. Wedge, D. J. Ogilvie, M. Dukes et al., “ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration,” Cancer Research, vol. 62, no. 16, pp. 4645–4655, 2002. View at Google Scholar · View at Scopus
  181. F. Carlomagno, D. Vitagliano, T. Guida et al., “ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases,” Cancer Research, vol. 62, no. 24, pp. 7284–7290, 2002. View at Google Scholar · View at Scopus
  182. M. Santoro and F. Carlomagno, “Drug insight: small-molecule inhibitors of protein kinases in the treatment of thyroid cancer,” Nature Clinical Practice Endocrinology and Metabolism, vol. 2, no. 1, pp. 42–52, 2006. View at Publisher · View at Google Scholar · View at Scopus
  183. F. Carlomagno, S. Anaganti, T. Guida et al., “BAY 43-9006 inhibition of oncogenic RET mutants,” Journal of the National Cancer Institute, vol. 98, no. 5, pp. 326–334, 2006. View at Publisher · View at Google Scholar · View at Scopus
  184. D. W. Kim, Y. S. Jo, H. S. Jung et al., “An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 10, pp. 4070–4076, 2006. View at Publisher · View at Google Scholar · View at Scopus
  185. S. Hoffmann, A. Burchert, A. Wunderlich et al., “Differential effects of cetuximab and AEE 788 on epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) in thyroid cancer cell lines,” Endocrine, vol. 31, no. 2, pp. 105–113, 2007. View at Publisher · View at Google Scholar · View at Scopus
  186. A. Polverino, A. Coxon, C. Starnes et al., “AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts,” Cancer Research, vol. 66, no. 17, pp. 8715–8721, 2006. View at Publisher · View at Google Scholar · View at Scopus
  187. D. Boughton, L. Rosen, A. Van Vugt et al., “Safety and antitumor activity of AMG 706 in patients with thyroid cancer: a subset analysis from a phase 1 dose-finding study,” Journal of Clinical Oncology, vol. 24, no. 18, supplement, p. 3030, 2006. View at Google Scholar
  188. H. Gharib and J. R. Goellner, “Fine-needle aspiration biopsy of the thyroid: an appraisal,” Annals of Internal Medicine, vol. 118, no. 4, pp. 282–289, 1993. View at Google Scholar · View at Scopus
  189. Y. Cohen, E. Rosenbaum, D. P. Clark et al., “Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid: a potential application for the preoperative assessment of thyroid nodules,” Clinical Cancer Research, vol. 10, no. 8, pp. 2761–2765, 2004. View at Publisher · View at Google Scholar · View at Scopus
  190. G. Salvatore, R. Giannini, P. Faviana et al., “Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 10, pp. 5175–5180, 2004. View at Publisher · View at Google Scholar · View at Scopus
  191. M. Xing, R. P. Tufano, A. P. Tufaro et al., “Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 6, pp. 2867–2872, 2004. View at Publisher · View at Google Scholar · View at Scopus
  192. K.-W. Chung, S. K. Yang, G. K. Lee et al., “Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis, especially in BRAFV600E mutation-prevalent area,” Clinical Endocrinology, vol. 65, no. 5, pp. 660–666, 2006. View at Publisher · View at Google Scholar · View at Scopus
  193. A. Kumagai, H. Namba, Z. Akanov et al., “Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer,” Endocrine Journal, vol. 54, no. 3, pp. 399–405, 2007. View at Publisher · View at Google Scholar · View at Scopus
  194. L. Jin, T. J. Sebo, N. Nakamura et al., “BRAF mutation analysis in fine needle aspiration (FNA) cytology of the thyroid,” Diagnostic Molecular Pathology, vol. 15, no. 3, pp. 136–143, 2006. View at Publisher · View at Google Scholar · View at Scopus
  195. D. Vitagliano, G. Portella, G. Troncone et al., “Thyroid targeting of the N-RAS(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas,” Oncogene, vol. 25, no. 39, pp. 5467–5474, 2006. View at Publisher · View at Google Scholar · View at Scopus
  196. M. N. Nikiforova, Z. Zhao Wen, T. Robinson-Smith et al., “Molecular testing of thyroid FNA samples: feasibility and significance for preoperative diagnosis of thyroid tumors (abstract),” Modern Pathology, vol. 17, supplement 1, p. 77A, 2004. View at Google Scholar
  197. R. Domingues, E. Mendoça, L. Sobrinho, and M. J. Bugalho, “Searching for RET/PTC rearrangements and BRAF V599E mutation in thyroid aspirates might contribute to establish a preoperative diagnosis of papillary thyroid carcinoma,” Cytopathology, vol. 16, no. 1, pp. 27–31, 2005. View at Publisher · View at Google Scholar · View at Scopus
  198. M. N. Nikiforova and Y. E Nikiforov, “Molecular genetics of thyroid cancer: implications for diagnosis, treatment and prognosis,” Expert Review of Molecular Diagnostics, vol. 8, no. 1, pp. 83–95, 2008. View at Publisher · View at Google Scholar · View at Scopus
  199. A. Bounacer, R. Wicker, B. Caillou et al., “High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation,” Oncogene, vol. 15, no. 11, pp. 1263–1273, 1997. View at Google Scholar · View at Scopus
  200. R. Elisei, C. Romei, T. Vorontsova et al., “RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 7, pp. 3211–3216, 2001. View at Publisher · View at Google Scholar · View at Scopus
  201. M. N. Nikiforova, C. M. Caudill, P. Biddinger, and Y. E. Nikiforov, “Prevalence of RET/PTC rearrangements in Hashimoto's thyroiditis and papillary thyroid carcinomas,” International Journal of Surgical Pathology, vol. 10, no. 1, pp. 15–22, 2002. View at Google Scholar · View at Scopus
  202. M. N. Nikiforova, P. W. Biddinger, C. M. Caudill, T. G. Kroll, and Y. E. Nikiforov, “PAX8-PPARγ rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses,” American Journal of Surgical Pathology, vol. 26, no. 8, pp. 1016–1023, 2002. View at Publisher · View at Google Scholar · View at Scopus
  203. P. Castro, A. P. Rebocho, R. J. Soares et al., “PAX8-PPAR? rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 1, pp. 213–220, 2006. View at Publisher · View at Google Scholar · View at Scopus
  204. K. S. Gustafson, V. A. LiVolsi, E. E. Furth, T. L. Pasha, M. E. Putt, and Z. W. Baloch, “Peroxisome proliferator-activated receptor γ expression in follicular-patterned thyroid lesions. Caveats for the use of immunohistochemical studies,” American Journal of Clinical Pathology, vol. 120, no. 2, pp. 175–181, 2003. View at Publisher · View at Google Scholar · View at Scopus