Skip to main content
SpringerLink
Log in

Molecular Pathogenesis of Thyroid Cancer and Oncogenes in Thyroid Cancer

  • Chapter
  • First Online:
Thyroid Cancer

Abstract

At the time of conception, the human organism is a single cell zygote. During the course of development into an adult, this cell expands into a complex mass of approximately 100 trillion cells, with an enormous variety of shapes, sizes, and functions. Normal tissue growth and development require prolific cell division, exquisitely regulated cell differentiation, and appropriately timed cell death or apoptosis. Neoplastic transformation of tissue generally occurs when abnormal regulatory mechanisms promote excessive cell division, impaired cell differentiation, and/or failure of apoptosis. In most tumor types, this aberrant control originates at the genetic level. Intensive study of these regulatory mechanisms has led to significant progress in our ability to diagnose, predict biological behavior, and understand the basic molecular pathophysiology of thyroid neoplasms. The upcoming sections explore the major advances in the study of thyroid oncogenes and tumor suppressor genes and address the clinical utility of these discoveries.

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover 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

References

  1. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, … Nikiforov YE. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 2006;30(2):216–22. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16434896.

    Google Scholar 

  2. Agrawal N, Jiao Y, Sausen M, Leary R, Bettegowda C, Roberts NJ, … Ball DW. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98(2):E364–9. doi:10.1210/jc.2012-2703.

    Google Scholar 

  3. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557–66. doi:10.1038/nm.3159.

    Article  CAS  PubMed  Google Scholar 

  4. Alberti L, Carniti C, Miranda C, Roccato E, Pierotti MA. RET and NTRK1 proto-oncogenes in human diseases. J Cell Physiol. 2003;195(2):168–86. doi:10.1002/jcp.10252.

    Article  CAS  PubMed  Google Scholar 

  5. Basolo F, Torregrossa L, Giannini R, Miccoli M, Lupi C, Sensi E, … Miccoli P. Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases. J Clin Endocrinol Metab. 2010;95(9):4197–205. doi:10.1210/jc.2010-0337.

    Google Scholar 

  6. Bedogni B, Welford SM, Kwan AC, Ranger-Moore J, Saboda K, Powell MB. Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model. Mol Cancer Ther. 2006;5(12):3071–7. doi:10.1158/1535-7163.MCT-06-0269.

    Article  CAS  PubMed  Google Scholar 

  7. Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH. BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol: Off J U S Can Acad Pathol Inc. 2004;17(11):1359–63. doi:10.1038/modpathol.3800198.

    Article  CAS  Google Scholar 

  8. Bishop JM. Cancer: the rise of the genetic paradigm. Genes Dev. 1995;9(11):1309–15. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7797071.

    Google Scholar 

  9. Boichard A, Croux L, Al Ghuzlan A, Broutin S, Dupuy C, Leboulleux S, … Lacroix L. Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid carcinomas and extend to a previously unidentified exon. J Clin Endocrinol Metab. 2012;97(10):E2031–5. doi:10.1210/jc.2012-2092.

    Google Scholar 

  10. Bongarzone I, Monzini N, Borrello MG, Carcano C, Ferraresi G, Arighi E, … Pierotti MA. Molecular characterization of a thyroid tumor-specific 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(1):358–66. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=358915&tool=pmcentrez&rendertype=abstract.

  11. Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytol. 2012;56(4):333–9. doi:10.1159/000339959.

    Article  PubMed  Google Scholar 

  12. Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, Suárez HG. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene. 1997;15(11):1263–73. doi:10.1038/sj.onc.1200206.

    Article  CAS  PubMed  Google Scholar 

  13. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, … Schlumberger MJ. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014. doi:10.1016/S0140-6736(14)60421-9.

    Google Scholar 

  14. Butti MG, Bongarzone I, Ferraresi G, Mondellini P, Borrello MG, Pierotti MA. A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas. Genomics. 1995;28(1):15–24. doi:10.1006/geno.1995.1100.

    Article  CAS  PubMed  Google Scholar 

  15. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676–90.

    Article  Google Scholar 

  16. Cantara S, Capezzone M, Marchisotta S, Capuano S, Busonero G, Toti P, … Pacini F. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J Clin Endocrinol Metab. 2010;95(3):1365–9. doi:10.1210/jc.2009-2103.

    Google Scholar 

  17. Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, … Santoro M. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004;23(36):6056–63. doi:10.1038/sj.onc.1207810.

    Google Scholar 

  18. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, … Santoro M. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62(24):7284–90. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12499271.

  19. Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, … Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA. 1994;91(4):1579–83. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=43203&tool=pmcentrez&rendertype=abstract.

  20. Carta C, Moretti S, Passeri L, Barbi F, Avenia N, Cavaliere A, … Puxeddu E. 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 (BRAF(V599lns)). Clin Endocrinol. 2006;64(1):105–9. doi:10.1111/j.1365-2265.2005.02401.x.

    Google Scholar 

  21. Chiosea S, Nikiforova M, Zuo H, Ogilvie J, Gandhi M, Seethala RR, … Nikiforov Y. A novel complex BRAF mutation detected in a solid variant of papillary thyroid carcinoma. Endocr Pathol. 2009;20(2):122–6. doi:10.1007/s12022-009-9073-3.

    Google Scholar 

  22. Ciampi R, Giordano TJ, Wikenheiser-Brokamp K, Koenig RJ, Nikiforov YE. HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr Relat Cancer. 2007;14(2):445–52. doi:10.1677/ERC-07-0039.

    Article  CAS  PubMed  Google Scholar 

  23. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, … Nikiforov YE. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Investig. 2005;115(1):94–101. doi:10.1172/JCI23237.

    Google Scholar 

  24. Ciampi R, Mian C, Fugazzola L, Cosci B, Romei C, Barollo S, … Elisei R. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid: Off J Am Thyroid Assoc. 2013;23(1):50–7. doi:10.1089/thy.2012.0207.

    Google Scholar 

  25. Cline MJ, Slamon DJ, Lipsick JS. Oncogenes: implications for the diagnosis and treatment of cancer. Ann Intern Med. 1984;101(2):223–33. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6331242.

    Google Scholar 

  26. Cohen Y, Rosenbaum E, Clark DP, Zeiger MA, Umbricht CB, Tufano RP, … Westra WH. Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid: a potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res: Off J Am Assoc Cancer Res. 2004;10(8):2761–5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15102681.

    Google Scholar 

  27. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, … Sidransky D. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95(8):625–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12697856.

    Google Scholar 

  28. Corvi R, Berger N, Balczon R, Romeo G. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene. 2000;19(37):4236–42. doi:10.1038/sj.onc.1203772.

    Article  CAS  PubMed  Google Scholar 

  29. Dahia PL, Marsh DJ, Zheng Z, Zedenius J, Komminoth P, Frisk T, … Eng C. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 1997;57(21):4710–3. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9354427.

  30. De Groot JWB, Links TP, Plukker JTM, Lips CJM, Hofstra RMW. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006;27(5):535–60. doi:10.1210/er.2006-0017.

    Article  PubMed  Google Scholar 

  31. Demeure MJ, Aziz M, Rosenberg R, Gurley SD, Bussey KJ, Carpten JD. Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target. World J Surg. 2014. doi:10.1007/s00268-014-2485-3.

    PubMed  Google Scholar 

  32. Dobashi Y, Sugimura H, Sakamoto A, Mernyei M, Mori M, Oyama T, Machinami R. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagn Mol Pathol: Am J Surg Pathol Part B. 1994;3(1):9–14. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8162258.

    Google Scholar 

  33. Dobson ME, Diallo-Krou E, Grachtchouk V, Yu J, Colby LA, Wilkinson JE, … Koenig RJ. Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma. Endocrinology. 2011;152(11):4455–65. doi:10.1210/en.2011-1178.

    Google Scholar 

  34. 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(4):1753–60. doi:10.1172/JCI116385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, … Wells SA. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851–6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8103403.

    Google Scholar 

  36. Druker BJ, Mamon HJ, Roberts TM. Oncogenes, growth factors, and signal transduction. N Engl J Med. 1989;321(20):1383–91. doi:10.1056/NEJM198911163212007.

    Article  CAS  PubMed  Google Scholar 

  37. Dwight T, Thoppe SR, Foukakis T, Lui WO, Wallin G, Höög A, … Zedenius J. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88(9):4440–5. doi:10.1210/jc.2002-021690.

    Google Scholar 

  38. Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, … Pinchera A. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008;93(3):682–7. doi:10.1210/jc.2007-1714.

    Google Scholar 

  39. Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E, … Pacini F. 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(7):3211–6. doi:10.1210/jcem.86.7.7678.

    Google Scholar 

  40. Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, … Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31(29):3639–46. doi:10.1200/JCO.2012.48.4659.

    Google Scholar 

  41. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, … Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA: J Am Med Assoc. 1996;276(19):1575–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8918855.

    Google Scholar 

  42. Eng C, Mulligan LM, Healey CS, Houghton C, Frilling A, Raue F, … Ponder BA. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res. 1996;56(9):2167–70. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8616867.

  43. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, … Wong K-K. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351–6. doi:10.1038/nm.1890.

    Google Scholar 

  44. Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol. 1999;50(4):529–35. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10468914.

    Google Scholar 

  45. Fagin JA. Clinical Investigator Award Lecture: Thyroid cancer: from genetics to biology to new treatment strategies. ENDO Society Meeting; 2014.

    Google Scholar 

  46. 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(1):179–84. doi:10.1172/JCI116168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Frank-Raue K, Buhr H, Dralle H, Klar E, Senninger N, Weber T, … Raue F. Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol/Eur Fed Endocr Soc. 2006;155(2):229–36. doi:10.1530/eje.1.02216.

    Google Scholar 

  48. Frank-Raue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Mol Cell Endocrinol. 2010;322(1–2):2–7. doi:10.1016/j.mce.2010.01.012.

    Article  CAS  PubMed  Google Scholar 

  49. French CA, Alexander EK, Cibas ES, Nose V, Laguette J, Faquin W, … Kroll TG. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol. 2003;162(4):1053–60. doi:10.1016/S0002-9440(10)63902-8.

    Google Scholar 

  50. Friend SH, Dryja TP, Weinberg RA. Oncogenes and tumor-suppressing genes. N Engl J Med. 1988;318(10):618–22. doi:10.1056/NEJM198803103181007.

    Article  CAS  PubMed  Google Scholar 

  51. Fugazzola L, Mannavola D, Cirello V, Vannucchi G, Muzza M, Vicentini L, Beck-Peccoz P. BRAF mutations in an Italian cohort of thyroid cancers. Clin Endocrinol. 2004;61(2):239–43. doi:10.1111/j.1365-2265.2004.02089.x.

    Article  CAS  Google Scholar 

  52. Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I. Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene. 1996;13(5):1093–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8806699.

  53. Fugazzola L, Pilotti S, Pinchera A, Vorontsova TV, Mondellini P, Bongarzone I, … Demidchik EP. Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res. 1995;55(23):5617–20. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7585643.

  54. Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, … Takenoshita S. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22(41):6455–7. doi:10.1038/sj.onc.1206739.

    Google Scholar 

  55. 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 CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Am J Pathol. 2001;158(3):987–96. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1850336&tool=pmcentrez&rendertype=abstract.

  56. García-Rostán G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R, Hermsem MJA, … Santoro M. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 2005;65(22):10199–207. doi:10.1158/0008-5472.CAN-04-4259.

    Google Scholar 

  57. Garcia-Rostan G, Tallini G, Herrero A, D’Aquila TG, Carcangiu ML, Rimm DL. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res. 1999;59(8):1811–5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10213482.

  58. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, … Benes CH. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5. doi:10.1038/nature11005.

    Google Scholar 

  59. Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, … Eng C. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82(11):3902–4. doi:10.1210/jcem.82.11.4508.

    Google Scholar 

  60. Godbert Y, Henriques de Figueiredo B, Bonichon F, Chibon F, Hostein I, Pérot G, … Soubeyran I. Remarkable response to crizotinib in woman with anaplastic lymphoma kinase-rearranged anaplastic thyroid carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol. 2014. doi:10.1200/JCO.2013.49.6596.

    Google Scholar 

  61. Gordon H. Oncogenes. Mayo Clin Proc. 1985;60(10):697–713. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2993762.

  62. Greco A, Mariani C, Miranda C, Lupas A, Pagliardini S, Pomati M, Pierotti MA. 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(11):6118–27. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=230863&tool=pmcentrez&rendertype=abstract.

  63. Greco A, Miranda C, Pagliardini S, Fusetti L, Bongarzone I, Pierotti MA. Chromosome 1 rearrangements involving the genes TPR and NTRK1 produce structurally different thyroid-specific TRK oncogenes. Gene Chromosome Cancer. 1997;19(2):112–23. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9172002.

    Google Scholar 

  64. Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol. 2010;321(1):44–9. doi:10.1016/j.mce.2009.10.009.

    Article  CAS  PubMed  Google Scholar 

  65. 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(2):237–42. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1532241.

  66. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, … Vecchio G. 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(4):557–63. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2406025.

    Google Scholar 

  67. Guerra A, Sapio MR, Marotta V, Campanile E, Moretti MI, Deandrea M, … Vitale M. Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application. Endocr J. 2011;58(1):31–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21173509.

    Google Scholar 

  68. Hamatani K, Eguchi H, Ito R, Mukai M, Takahashi K, Taga M, … Nakachi K. RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. Cancer Res. 2008;68(17):7176–82. doi:10.1158/0008-5472.CAN-08-0293.

    Google Scholar 

  69. Hamatani K, Mukai M, Takahashi K, Hayashi Y, Nakachi K, Kusunoki Y. Rearranged anaplastic lymphoma kinase (ALK) gene in adult-onset papillary thyroid cancer amongst atomic bomb survivors. Thyroid: Off J Am Thyroid Assoc. 2012;22(11):1153–9. doi:10.1089/thy.2011.0511.

    Article  CAS  Google Scholar 

  70. Hartwell LH, Kastan MB. Cell cycle control and cancer. Science (New York, NY). 1994;266(5192):1821–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7997877.

    Google Scholar 

  71. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, … Romeo G. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375–6. doi:10.1038/367375a0.

    Google Scholar 

  72. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, … Kumar R. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959–61. doi:10.1126/science.1230062.

    Google Scholar 

  73. Hou P, Liu D, Shan Y, Hu S, Studeman K, Condouris S, … Xing M. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13(4):1161–70. doi:10.1158/1078-0432.CCR-06-1125.

    Google Scholar 

  74. Hou P, Liu D, Xing M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle (Georgetown, Tex). 2007;6(3):377–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17297294.

    Google Scholar 

  75. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science (New York, NY). 2013;339(6122):957–9. doi:10.1126/science.1229259.

    Article  CAS  Google Scholar 

  76. Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett. 2004;204(2):197–211. doi:10.1016/S0304-3835(03)00456-7.

    Article  CAS  PubMed  Google Scholar 

  77. 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(9):1667–72. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1717926.

  78. Ito T, Seyama T, Mizuno T, Tsuyama N, Hayashi T, Hayashi Y, … Akiyama M. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res. 1992;52(5):1369–71. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1737400.

  79. Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, … Takahashi M. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun. 2000;268(3):804–8. doi:10.1006/bbrc.2000.2227.

    Google Scholar 

  80. Jhiang SM. The RET proto-oncogene in human cancers. Oncogene. 2000;19(49):5590–7. doi:10.1038/sj.onc.1203857.

    Article  CAS  PubMed  Google Scholar 

  81. Jia Y, Yu Y, Li X, Wei S, Zheng X, Yang X, … Gao M. Diagnostic value of B-RAF(V600E) in difficult-to-diagnose thyroid nodules using fine-needle aspiration: systematic review and meta-analysis. Diagn Cytopathol. 2014;42(1):94–101. doi:10.1002/dc.23044.

    Google Scholar 

  82. Kelly LM, Barila G, Liu P, Evdokimova VN, Trivedi S, Panebianco F, … Nikiforov YE. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci USA. 2014;111(11):4233–8. doi:10.1073/pnas.1321937111.

    Google Scholar 

  83. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. 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 Res. 2003;63(7):1454–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12670889.

  84. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, … Wells SA. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid: Off J Am Thyroid Assoc. 2009;19(6):565–612. doi:10.1089/thy.2008.0403.

    Google Scholar 

  85. 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(2):198–203. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9443391.

  86. 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(24):7028–32. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11156407.

  87. 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(12):2459–67. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8545102.

  88. 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(30):4388–93. doi:10.1038/sj.onc.1202824.

    Article  CAS  PubMed  Google Scholar 

  89. Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci U S A. 1993;90(23):10914–21. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=47892&tool=pmcentrez&rendertype=abstract.

  90. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science (New York, NY). 2000;289(5483):1357–60. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10958784.

    Google Scholar 

  91. Krontiris TG. Oncogenes. N Engl J Med. 1995;333(5):303–6. doi:10.1056/NEJM199508033330508.

    Article  CAS  PubMed  Google Scholar 

  92. Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, … Fagin JA. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab. 2013;98(9):E1562–6. doi:10.1210/jc.2013-2383.

    Google Scholar 

  93. Latchman DS. Transcription-factor mutations and disease. N Engl J Med. 1996;334(1):28–33. doi:10.1056/NEJM199601043340108.

    Article  CAS  PubMed  Google Scholar 

  94. Leeman-Neill RJ, Brenner AV, Little MP, Bogdanova TI, Hatch M, Zurnadzy LY, … Nikiforov YE. RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics. Cancer. 2013;119(10):1792–9. doi:10.1002/cncr.27893.

    Google Scholar 

  95. Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, … Nikiforov YE. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2013. doi:10.1002/cncr.28484.

    Google Scholar 

  96. Lemoine NR, Mayall ES, Wyllie FS, Williams ED, Goyns M, Stringer B, Wynford-Thomas D. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989;4(2):159–64. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2648253.

  97. Li C, Lee KC, Schneider EB, Zeiger MA. BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab. 2012;97(12):4559–70. doi:10.1210/jc.2012-2104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, … Nikiforov YE. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014. doi:10.1002/cncr.28484.

    Google Scholar 

  99. Lui W-O, Zeng L, Rehrmann V, Deshpande S, Tretiakova M, Kaplan EL, … Kroll TG. CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Res. 2008;68(17):7156–64. doi:10.1158/0008-5472.CAN-08-1085.

    Google Scholar 

  100. Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher H-D, … Dralle H. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349(16):1517–25. doi:10.1056/NEJMoa012915.

    Google Scholar 

  101. Marques AR, Espadinha C, Catarino AL, Moniz S, Pereira T, Sobrinho LG, Leite V. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab. 2002;87(8):3947–52. doi:10.1210/jcem.87.8.8756.

    CAS  PubMed  Google Scholar 

  102. Marshall CJ. Tumor suppressor genes. Cell. 1991;64(2):313–26. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1988150.

    Google Scholar 

  103. Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, … Soares P. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014;99(5):E754–65. doi:10.1210/jc.2013-3734.

    Google Scholar 

  104. Menko FH, van der Luijt RB, de Valk IAJ, Toorians AWFT, Sepers JM, van Diest PJ, Lips CJM. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab. 2002;87(1):393–7. doi:10.1210/jcem.87.1.8136.

    Article  CAS  PubMed  Google Scholar 

  105. Minoletti F, Butti MG, Coronelli S, Miozzo M, Sozzi G, Pilotti S, … Bongarzone I. The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Gene Chromosome Cancer. 1994;11(1):51–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7529046.

    Google Scholar 

  106. Mologni L, Redaelli S, Morandi A, Plaza-Menacho I, Gambacorti-Passerini C. Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. Mol Cell Endocrinol. 2013;377(1–2):1–6. doi:10.1016/j.mce.2013.06.025.

    Article  CAS  PubMed  Google Scholar 

  107. Moura MM, Cavaco BM, Pinto AE, Leite V. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 2011;96(5):E863–8. doi:10.1210/jc.2010-1921.

    Article  CAS  PubMed  Google Scholar 

  108. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, … Papi L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458–60. doi:10.1038/363458a0.

    Google Scholar 

  109. Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71(13):4403–11. doi:10.1158/0008-5472.CAN-10-4041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nakata T, Kitamura Y, Shimizu K, Tanaka S, Fujimori M, Yokoyama S, … Emi M. Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma. Gene Chromosome Cancer. 1999;25(2):97–103. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10337992.

    Google Scholar 

  111. 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(9):1690–4. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9135009.

  112. Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, … Nikiforova MN. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009;94(6):2092–8. doi:10.1210/jc.2009-0247.

    Google Scholar 

  113. Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol. 2002;26(8):1016–23. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12170088.

  114. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, … Nikiforov YE. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2003;88(11):5399–404. doi:10.1210/jc.2003-030838.

    Google Scholar 

  115. Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW, Tallini G, … Nikiforov YE. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab. 2003;88(5):2318–26. doi:10.1210/jc.2002-021907.

    Google Scholar 

  116. Nikiforova MN, Wald AI, Roy S, Durso MB, Nikiforov YE. Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab. 2013;98(11):E1852–60. doi:10.1210/jc.2013-2292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pierotti MA, Santoro M, Jenkins RB, Sozzi G, Bongarzone I, Grieco M, … Fusco A. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA. 1992;89(5):1616–20. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=48503&tool=pmcentrez&rendertype=abstract.

  118. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. doi:10.3389/fonc.2014.00064.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res: Off J Am Assoc Cancer Res. 2000;6(3):1093–103. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10741739.

  120. Raman P, Koenig RJ. Pax-8-PPAR-γ fusion protein in thyroid carcinoma. Nat Rev Endocrinol. 2014. doi:10.1038/nrendo.2014.115.

    PubMed  PubMed Central  Google Scholar 

  121. Ricarte-Filho JC, Li S, Garcia-Rendueles MER, Montero-Conde C, Voza F, Knauf JA, … Fagin JA. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Investig. 2013;123(11):4935–44. doi:10.1172/JCI69766.

    Google Scholar 

  122. Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, … Fagin JA. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009;69(11):4885–93. doi:10.1158/0008-5472.CAN-09-0727.

    Google Scholar 

  123. Rivera M, Ricarte-Filho J, Knauf J, Shaha A, Tuttle M, Fagin JA, Ghossein RA. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol: Off J U S Can Acad Pathol Inc. 2010;23(9):1191–200. doi:10.1038/modpathol.2010.112.

    Article  CAS  Google Scholar 

  124. Saenko V, Rogounovitch T, Shimizu-Yoshida Y, Abrosimov A, Lushnikov E, Roumiantsev P, … Yamashita S. Novel tumorigenic rearrangement, delta rfp/ret, in a papillary thyroid carcinoma from externally irradiated patient. Mutat Research. 2003;527(1–2):81–90. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12787916.

  125. Salassidis K, Bruch J, Zitzelsberger H, Lengfelder E, Kellerer AM, Bauchinger M. Translocation t(10;14)(q11.2: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(11):2786–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10850414.

  126. Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI. Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab. 2008;93(1):278–84. doi:10.1210/jc.2007-1076.

    Article  CAS  PubMed  Google Scholar 

  127. Santelli G, de Franciscis V, Portella G, Chiappetta G, D’Alessio A, Califano D, … Manzo G. Production of transgenic mice expressing the Ki-ras oncogene under the control of a thyroglobulin promoter. Cancer Res. 1993;53(22):5523–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8221693.

  128. Santoro M, Carlomagno F, Hay ID, Herrmann MA, Grieco M, Melillo R, … Berger N. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Investig. 1992;89(5):1517–22. doi:10.1172/JCI115743.

    Google Scholar 

  129. Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, … Fusco A. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene. 1994;9(2):509–16. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8290261.

  130. Sapio MR, Guerra A, Marotta V, Campanile E, Formisano R, Deandrea M, … Vitale M. High growth rate of benign thyroid nodules bearing RET/PTC rearrangements. J Clin Endocrinol Metab. 2011;96(6):E916–9. doi:10.1210/jc.2010-1599.

    Google Scholar 

  131. Schilling T, Bürck J, Sinn HP, Clemens A, Otto HF, Höppner W, … Raue F. Prognostic value of codon 918 (ATG–>ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. J Int Cancer. 2001;95(1):62–6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11241313.

  132. Skelhorne-Gross G, Nicol CJB. The key to unlocking the chemotherapeutic potential of PPARγ ligands: having the right combination. PPAR Res. 2012;2012:946943. doi:10.1155/2012/946943.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med. 2005;353(11):1105–13. doi:10.1056/NEJMoa043999.

    Article  CAS  PubMed  Google Scholar 

  134. Smallridge RC, Chindris A-M, Asmann YW, Casler JD, Serie DJ, Reddi HV, … Aubrey Thompson E. RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-type papillary thyroid carcinoma. J Clin Endocrinol Metab. 2014;99(2):E338–47. doi:10.1210/jc.2013-2792.

    Google Scholar 

  135. Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, … Sobrinho-Simões M. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22(29):4578–80. doi:10.1038/sj.onc.1206706.

    Google Scholar 

  136. Takahashi K, Eguchi H, Arihiro K, Ito R, Koyama K, Soda M, … Hamatani K. The presence of BRAF point mutation in adult papillary thyroid carcinomas from atomic bomb survivors correlates with radiation dose. Mol Carcinog. 2007;46(3):242–8. doi:10.1002/mc.20277.

    Google Scholar 

  137. Trovisco V, Soares P, Soares R, Magalhães J, Sá-Couto P, Sobrinho-Simões M. A new BRAF gene mutation detected in a case of a solid variant of papillary thyroid carcinoma. Hum Pathol. 2005;36(6):694–7. doi:10.1016/j.humpath.2005.04.011.

    Article  CAS  PubMed  Google Scholar 

  138. Trovisco V, Vieira de Castro I, Soares P, Máximo V, Silva P, Magalhães J, … Sobrinho-Simões M. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004;202(2):247–51. doi:10.1002/path.1511.

    Google Scholar 

  139. Tufano RP, Teixeira GV, Bishop J, Carson KA, Xing M. BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine. 2012;91(5):274–86. doi:10.1097/MD.0b013e31826a9c71.

    Article  CAS  PubMed  Google Scholar 

  140. Tuttle RM, Ball DW, Byrd D, Dickson P, Duh Q-Y, Ehya H, … Hunt JP. NCCN clinical practice guidelines in oncology (NCCN guidelines®) thyroid carcinoma. 2013.

    Google Scholar 

  141. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet: TIG. 1993;9(4):138–41. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8516849.

  142. Weinberg RA. Tumor suppressor genes. Science (New York, NY). 1991;254(5035):1138–46. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1659741.

    Google Scholar 

  143. Weinberg RA. How cancer arises. Sci Am. 1996;275(3):62–70. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8701295.

    Google Scholar 

  144. Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, … Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(2):134–41. doi:10.1200/JCO.2011.35.5040.

    Google Scholar 

  145. Wells SA, Santoro M. Targeting the RET pathway in thyroid cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15(23):7119–23. doi:10.1158/1078-0432.CCR-08-2742.

    Article  CAS  Google Scholar 

  146. Wirtschafter A, Schmidt R, Rosen D, Kundu N, Santoro M, Fusco A, … Rothstein JL. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope. 1997;107(1):95–100. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9001272.

    Google Scholar 

  147. Wood WM, Sharma V, Bauerle KT, Pike LA, Zhou Q, Fretwell DL, … Haugen BR. PPARγ promotes growth and invasion of thyroid cancer cells. PPAR Res. 2011;2011:171765. doi:10.1155/2011/171765.

    Google Scholar 

  148. Xing M. BRAF mutation in thyroid cancer. Endocrine Relat Cancer. 2005;12(2):245–62. doi:10.1677/erc.1.0978.

    Article  CAS  Google Scholar 

  149. Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, … Sykorova V. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA: J Am Med Assoc. 2013;309(14):1493–501. doi:10.1001/jama.2013.3190.

    Google Scholar 

  150. Xu X, Quiros RM, Gattuso P, Ain KB, Prinz RA. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 2003;63(15):4561–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12907632.

  151. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, … Joly AH. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308. doi:10.1158/1535-7163.MCT-11-0264.

    Google Scholar 

  152. Zedenius J, Larsson C, Bergholm U, Bovée J, Svensson A, Hallengren B, … Wallin G. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 1995;80(10):3088–90. doi:10.1210/jcem.80.10.7559902.

    Google Scholar 

  153. Zedenius J, Wallin G, Hamberger B, Nordenskjöld M, Weber G, Larsson C. Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC:s. Hum Mol Genet. 1994;3(8):1259–62. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7987299.

    Google Scholar 

  154. Zhang Z, Liu D, Murugan AK, Liu Z, Xing M. Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer. Endocrine Relat Cancer. 2014;21(2):161–73. doi:10.1530/ERC-13-0399.

    Article  Google Scholar 

  155. Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J Clin Endocrinol Metab. 2006;91(9):3603–10. doi:10.1210/jc.2006-1006.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado, MS 8106, 12801 E. 17th Ave, RC1-South, Room 7103, Aurora, CO, 80045, USA

    Nikita Pozdeyev MD, PhD

  2. Denver Endocrinology Diabetes & Thyroid Center, Swedish Medical Center, Englewood, CO, USA

    Gregory Lund MD

  3. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado, MS 8106, 12801 E. 17th Ave, RC1-South, Room 7103, Aurora, 80045, CO, USA

    Michael T. McDermott MD

Authors
  1. Nikita Pozdeyev MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory Lund MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael T. McDermott MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nikita Pozdeyev MD, PhD .

Editor information

Editors and Affiliations

  1. Department of Medicine, MedStar Washington Hospital Center Georgetown University School of Medicine, Washington, DC, USA

    Leonard Wartofsky

  2. Nuclear Medicine Research MedStar Research Institute and Washington Hospital Center, Georgetown University School of Medicine Washington Hospital Center, Washington, DC, USA

    Douglas Van Nostrand

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this chapter

Cite this chapter

Pozdeyev, N., Lund, G., McDermott, M.T. (2016). Molecular Pathogenesis of Thyroid Cancer and Oncogenes in Thyroid Cancer. In: Wartofsky, L., Van Nostrand, D. (eds) Thyroid Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3314-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3314-3_3

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-3312-9

  • Online ISBN: 978-1-4939-3314-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation