Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer

Carl D Malchoff, MD
Section Editor
Douglas S Ross, MD
Deputy Editor
Jean E Mulder, MD


A thyroid tumor develops when the growth of a single thyroid epithelial cell escapes from the normal mechanisms regulating cell division and gains a selective growth advantage. Continued growth leads in time to a clinically evident tumor mass. Unregulated cell division can result from mutations in both oncogenes and tumor suppressor genes.

Although thyroid epithelial tumors arise from the same cell type, they have diverse clinical characteristics. Most produce less thyroid hormone than normal thyroid tissue, but a few produce more. Most are adenomas, but some are slow-growing cancers, and a few are highly aggressive cancers.

An understanding of the mutations of the proto-oncogenes and tumor suppressor genes that occur in these tumors may explain the diverse clinical characteristics of thyroid tumors, provide diagnostic information, and direct therapy. Some insights have already emerged; some abnormalities in tumor genes are consistently associated with specific clinical and pathologic findings. These genetic abnormalities usually represent somatic (acquired) mutations, as opposed to inherited (germline) mutations. Most thyroid tumors are sporadic and not familial. This is different from the multiple endocrine neoplasia (MEN) syndromes in which the primary tumorigenic gene mutations are inherited. (See "Classification and genetics of multiple endocrine neoplasia type 2".)

This topic review will discuss the tumorigenic gene changes found in thyroid epithelial (nonmedullary) tumors. A summary of these changes is found in the table (table 1). Medullary thyroid cancer is included in this table for comparison but is discussed elsewhere, as are the characteristics and treatment of the specific tumors. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging" and "Medullary thyroid cancer: Treatment and prognosis" and "Papillary thyroid cancer" and "Follicular thyroid cancer (including Hürthle cell cancer)" and "Anaplastic thyroid cancer".)


Autonomously functioning thyroid adenomas (or nodules) are benign tumors that produce thyroid hormone. Clinically, they present as a single nodule that is hyperfunctioning ("hot") on thyroid radionuclide scan, sometimes causing hyperthyroidism. (See "Diagnostic approach to and treatment of thyroid nodules".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Aug 09, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Porcellini A, Ruggiano G, Pannain S, et al. Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells. Oncogene 1997; 15:781.
  2. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993; 365:649.
  3. Paschke R, Tonacchera M, Van Sande J, et al. Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid. J Clin Endocrinol Metab 1994; 79:1785.
  4. Porcellini A, Ciullo I, Laviola L, et al. Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning adenomas. Rapid identification by fine needle aspiration biopsy. J Clin Endocrinol Metab 1994; 79:657.
  5. Russo D, Arturi F, Wicker R, et al. Genetic alterations in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 1995; 80:1347.
  6. Russo D, Arturi F, Suarez HG, et al. Thyrotropin receptor gene alterations in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 1996; 81:1548.
  7. Führer D, Holzapfel HP, Wonerow P, et al. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 1997; 82:3885.
  8. Kopp P, van Sande J, Parma J, et al. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995; 332:150.
  9. O'Sullivan C, Barton CM, Staddon SL, et al. Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinog 1991; 4:345.
  10. Suarez HG, du Villard JA, Caillou B, et al. gsp mutations in human thyroid tumours. Oncogene 1991; 6:677.
  11. Lyons J, Landis CA, Harsh G, et al. Two G protein oncogenes in human endocrine tumors. Science 1990; 249:655.
  12. Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A 1992; 89:5152.
  13. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325:1688.
  14. Malchoff CD, Reardon G, MacGillivray DC, et al. An unusual presentation of McCune-Albright syndrome confirmed by an activating mutation of the Gs alpha-subunit from a bone lesion. J Clin Endocrinol Metab 1994; 78:803.
  15. Mastorakos G, Mitsiades NS, Doufas AG, Koutras DA. Hyperthyroidism in McCune-Albright syndrome with a review of thyroid abnormalities sixty years after the first report. Thyroid 1997; 7:433.
  16. Ramelli F, Studer H, Bruggisser D. Pathogenesis of thyroid nodules in multinodular goiter. Am J Pathol 1982; 109:215.
  17. Apel RL, Ezzat S, Bapat BV, et al. Clonality of thyroid nodules in sporadic goiter. Diagn Mol Pathol 1995; 4:113.
  18. Aeschimann S, Kopp PA, Kimura ET, et al. Morphological and functional polymorphism within clonal thyroid nodules. J Clin Endocrinol Metab 1993; 77:846.
  19. Bignell GR, Canzian F, Shayeghi M, et al. Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. Am J Hum Genet 1997; 61:1123.
  20. Namba H, Matsuo K, Fagin JA. Clonal composition of benign and malignant human thyroid tumors. J Clin Invest 1990; 86:120.
  21. Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989; 4:159.
  22. Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol 1990; 4:1474.
  23. Suarez HG, du Villard JA, Severino M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990; 5:565.
  24. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989; 49:4682.
  25. Karga H, Lee JK, Vickery AL Jr, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991; 73:832.
  26. Bounacer A, Wicker R, Caillou B, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 1997; 15:1263.
  27. Belge G, Rippe V, Meiboom M, et al. Delineation of a 150-kb breakpoint cluster in benign thyroid tumors with 19q13.4 aberrations. Cytogenet Cell Genet 2001; 93:48.
  28. Rippe V, Drieschner N, Meiboom M, et al. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene 2003; 22:6111.
  29. Kimura ET, Nikiforova MN, Zhu Z, et al. 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; 63:1454.
  30. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159:676.
  31. Indo Y, Mardy S, Tsuruta M, et al. Structure and organization of the human TRKA gene encoding a high affinity receptor for nerve growth factor. Jpn J Hum Genet 1997; 42:343.
  32. Jhiang SM, Sagartz JE, Tong Q, et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 1996; 137:375.
  33. Santoro M, Chiappetta G, Cerrato A, et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 1996; 12:1821.
  34. Bongarzone I, Vigneri P, Mariani L, et al. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res 1998; 4:223.
  35. Nikiforov YE, Rowland JM, Bove KE, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997; 57:1690.
  36. Bongarzone I, Fugazzola L, Vigneri P, et al. Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. J Clin Endocrinol Metab 1996; 81:2006.
  37. Bongarzone I, Butti MG, Fugazzola L, et al. Comparison of the breakpoint regions of ELE1 and RET genes involved in the generation of RET/PTC3 oncogene in sporadic and in radiation-associated papillary thyroid carcinomas. Genomics 1997; 42:252.
  38. Greco A, Miranda C, Pagliardini S, et al. Chromosome 1 rearrangements involving the genes TPR and NTRK1 produce structurally different thyroid-specific TRK oncogenes. Genes Chromosomes Cancer 1997; 19:112.
  39. Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990; 60:557.
  40. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. A new form of RET rearrangement in thyroid carcinomas of children after the Chernobyl reactor accident. Oncogene 1996; 13:1099.
  41. Fugazzola L, Pierotti MA, Vigano E, et al. 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; 13:1093.
  42. Wynford-Thomas D. Origin and progression of thyroid epithelial tumours: cellular and molecular mechanisms. Horm Res 1997; 47:145.
  43. Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003; 95:625.
  44. Cohen Y, Rosenbaum E, Clark DP, et al. 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 2004; 10:2761.
  45. Fugazzola L, Mannavola D, Cirello V, et al. BRAF mutations in an Italian cohort of thyroid cancers. Clin Endocrinol (Oxf) 2004; 61:239.
  46. Knauf JA, Ma X, Smith EP, et al. Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 2005; 65:4238.
  47. Lupi C, Giannini R, Ugolini C, et al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 2007; 92:4085.
  48. Caronia LM, Phay JE, Shah MH. Role of BRAF in thyroid oncogenesis. Clin Cancer Res 2011; 17:7511.
  49. Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 2013; 309:1493.
  50. Kim TH, Park YJ, Lim JA, et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer 2012; 118:1764.
  51. Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005; 90:6373.
  52. Cappola AR, Mandel SJ. Molecular testing in thyroid cancer: BRAF mutation status and mortality. JAMA 2013; 309:1529.
  53. Vasko V, Hu S, Wu G, et al. High prevalence and possible de novo formation of BRAF mutation in metastasized papillary thyroid cancer in lymph nodes. J Clin Endocrinol Metab 2005; 90:5265.
  54. Oler G, Ebina KN, Michaluart P Jr, et al. Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis reveals a new mutation in metastasis. Clin Endocrinol (Oxf) 2005; 62:509.
  55. Lima J, Trovisco V, Soares P, et al. BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 2004; 89:4267.
  56. Kumagai A, Namba H, Saenko VA, et al. Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab 2004; 89:4280.
  57. Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 2005; 115:94.
  58. Cradic KW, Milosevic D, Rosenberg AM, et al. Mutant BRAF(T1799A) can be detected in the blood of papillary thyroid carcinoma patients and correlates with disease status. J Clin Endocrinol Metab 2009; 94:5001.
  59. Salerno P, De Falco V, Tamburrino A, et al. Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells. J Clin Endocrinol Metab 2010; 95:450.
  60. Ball DW. Selectively targeting mutant BRAF in thyroid cancer. J Clin Endocrinol Metab 2010; 95:60.
  61. Zhu Z, Gandhi M, Nikiforova MN, et al. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 2003; 120:71.
  62. Fagin JA, Mitsiades N. Molecular pathology of thyroid cancer: diagnostic and clinical implications. Best Pract Res Clin Endocrinol Metab 2008; 22:955.
  63. Liu X, Qu S, Liu R, et al. TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab 2014; 99:E1130.
  64. He H, Jazdzewski K, Li W, et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci U S A 2005; 102:19075.
  65. Cong D, He M, Chen S, et al. Expression profiles of pivotal microRNAs and targets in thyroid papillary carcinoma: an analysis of The Cancer Genome Atlas. Onco Targets Ther 2015; 8:2271.
  66. Jazdzewski K, Murray EL, Franssila K, et al. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A 2008; 105:7269.
  67. Jazdzewski K, Liyanarachchi S, Swierniak M, et al. Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proc Natl Acad Sci U S A 2009; 106:1502.
  68. Gudmundsson J, Sulem P, Gudbjartsson DF, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 2009; 41:460.
  69. Sturgis EM, Zhao C, Zheng R, Wei Q. Radiation response genotype and risk of differentiated thyroid cancer: a case-control analysis. Laryngoscope 2005; 115:938.
  70. Cybulski C, Górski B, Huzarski T, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 2004; 75:1131.
  71. Adjadj E, Schlumberger M, de Vathaire F. Germ-line DNA polymorphisms and susceptibility to differentiated thyroid cancer. Lancet Oncol 2009; 10:181.
  72. Bastos HN, Antão MR, Silva SN, et al. Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk. Thyroid 2009; 19:1067.
  73. Hu S, Liu D, Tufano RP, et al. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer 2006; 119:2322.
  74. Xing M. Gene methylation in thyroid tumorigenesis. Endocrinology 2007; 148:948.
  75. Shi Y, Zou M, Farid NR, al-Sedairy ST. Evidence of gene deletion of p21 (WAF1/CIP1), a cyclin-dependent protein kinase inhibitor, in thyroid carcinomas. Br J Cancer 1996; 74:1336.
  76. Giardiello FM, Offerhaus GJ, Lee DH, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 1993; 34:1394.
  77. Zeki K, Spambalg D, Sharifi N, et al. Mutations of the adenomatous polyposis coli gene in sporadic thyroid neoplasms. J Clin Endocrinol Metab 1994; 79:1317.
  78. Cetta F, Chiappetta G, Melillo RM, et al. The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas. J Clin Endocrinol Metab 1998; 83:1003.
  79. Houlston RS, Stratton MR. Genetics of non-medullary thyroid cancer. QJM 1995; 88:685.
  80. Loh KC. Familial nonmedullary thyroid carcinoma: a meta-review of case series. Thyroid 1997; 7:107.
  81. Malchoff CD, Malchoff DM. Familial nonmedullary thyroid carcinoma. Semin Surg Oncol 1999; 16:16.
  82. Malchoff CD, Malchoff DM. The genetics of hereditary nonmedullary thyroid carcinoma. J Clin Endocrinol Metab 2002; 87:2455.
  83. He H, Li W, Wu D, et al. Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance. PLoS One 2013; 8:e61920.
  84. Hishinuma A, Fukata S, Kakudo K, et al. High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations. Thyroid 2005; 15:1079.
  85. Malchoff CD, Sarfarazi M, Tendler B, et al. Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab 2000; 85:1758.
  86. McKay JD, Lesueur F, Jonard L, et al. Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21. Am J Hum Genet 2001; 69:440.
  87. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000; 289:1357.
  88. Marques AR, Espadinha C, Catarino AL, et al. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2002; 87:3947.
  89. Terrier P, Sheng ZM, Schlumberger M, et al. Structure and expression of c-myc and c-fos proto-oncogenes in thyroid carcinomas. Br J Cancer 1988; 57:43.
  90. Ward LS, Brenta G, Medvedovic M, Fagin JA. Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab 1998; 83:525.
  91. Ngeow J, Mester J, Rybicki LA, et al. Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab 2011; 96:E2063.
  92. Xing M, Cohen Y, Mambo E, et al. Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Cancer Res 2004; 64:1664.
  93. Máximo V, Botelho T, Capela J, 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. Br J Cancer 2005; 92:1892.
  94. Gasparre G, Porcelli AM, Bonora E, et al. Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors. Proc Natl Acad Sci U S A 2007; 104:9001.
  95. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol 2016; 2:1023.
  96. Lee SE, Hwang TS, Choi YL, et al. Molecular Profiling of Papillary Thyroid Carcinoma in Korea with a High Prevalence of BRAF(V600E) Mutation. Thyroid 2017; 27:802.
  97. Jiang XS, Harrison GP, Datto MB. Young Investigator Challenge: Molecular testing in noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Cancer 2016; 124:893.
  98. Fagin JA, Matsuo K, Karmakar A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 91:179.
  99. Shi X, Liu R, Qu S, et al. Association of TERT promoter mutation 1,295,228 C>T with BRAF V600E mutation, older patient age, and distant metastasis in anaplastic thyroid cancer. J Clin Endocrinol Metab 2015; 100:E632.
  100. Quiros RM, Ding HG, Gattuso P, et al. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 2005; 103:2261.
  101. Landa I, Ibrahimpasic T, Boucai L, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 2016; 126:1052.
  102. Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 1998; 4:287.
  103. Garcia-Rostan G, Camp RL, Herrero A, et al. 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; 158:987.
  104. García-Rostán G, Costa AM, Pereira-Castro I, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res 2005; 65:10199.
  105. Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res 2011; 71:4403.