Thyroid cancer is a common type of endocrine malignancy, and its incidence has been steadily increasing in many regions of the world. Initiation and progression of thyroid cancer involves multiple genetic and epigenetic alterations, of which mutations leading to the activation of the MAPK and PI3K–AKT signaling pathways are crucial. Common mutations found in thyroid cancer are point mutation of the BRAF and RAS genes as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements. The mutational mechanisms seem to be linked to specific etiologic factors. Chromosomal rearrangements have a strong association with exposure to ionizing radiation and possibly with DNA fragility, whereas point mutations probably arise as a result of chemical mutagenesis. A potential role of dietary iodine excess in the generation of BRAF point mutations has also been proposed. Somatic mutations and other molecular alterations have been recognized as helpful diagnostic and prognostic markers for thyroid cancer and are beginning to be introduced into clinical practice, to offer a valuable tool for the management of patients with thyroid nodules.
Activation of MAPK and PI3K–AKT signaling pathways is important for thyroid cancer initiation and progression
Common mutational mechanisms in thyroid cancer are point mutations, such as those in the RAS and BRAF genes, and chromosomal rearrangements, such as RET/PTC and PAX8/PPARγ
RET/PTC and BRAF/AKAP9 chromosomal rearrangements have strong correlation with radiation exposure; RET/PTC can also develop via induction of chromosome fragility
Association between BRAF point mutations and high iodine intake or exposure to chemical elements present at high levels in volcanic areas has been proposed
Mutational markers can be used to improve cancer diagnosis in fine-needle aspiration samples from thyroid nodules and to aid tumor prognostication
Your institute does not have access to this article
Open Access articles citing this article.
SGSM2 inhibits thyroid cancer progression by activating RAP1 and enhancing competitive RAS inhibition
Cell Death & Disease Open Access 09 March 2022
An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks
Molecular Cancer Open Access 08 September 2021
World Journal of Surgical Oncology Open Access 29 July 2021
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
DeLellis, R. A., Lloyd, R. V., Heitz, P. U. & Eng, C. (Eds) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs (IARC Press, Lyon, 2004).
Nikiforov, Y. E. in Diagnostic Pathology and Molecular Genetics of the Thyroid (eds Nikiforov, Y. E., Biddinger, P. W. & Thompson, L. D. R.) 94–102 (Lippincott Williams & Wilkins, Baltimore, 2009).
Davies, L. & Welch, H. G. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 295, 2164–2167 (2006).
Albores-Saavedra, J., Henson, D. E., Glazer, E. & Schwartz, A. M. Changing patterns in the incidence and survival of thyroid cancer with follicular phenotype–papillary, follicular, and anaplastic: a morphological and epidemiological study. Endocr. Pathol. 18, 1–7 (2007).
Burgess, J. R. & Tucker, P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid 16, 47–53 (2006).
Colonna, M. et al. A time trend analysis of papillary and follicular cancers as a function of tumour size: a study of data from six cancer registries in France (1983–2000). Eur. J. Cancer 43, 891–900 (2007).
Mazzaferri, E. L. Thyroid cancer in thyroid nodules: finding a needle in the haystack. Am. J. Med. 93, 359–362 (1992).
Gharib, H. Changing trends in thyroid practice: understanding nodular thyroid disease. Endocr. Pract. 10, 31–39 (2004).
Frates, M. C. et al. Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J. Clin. Endocrinol. Metab. 91, 3411–3417 (2006).
Papini, E. et al. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J. Clin. Endocrinol. Metab. 87, 1941–1946 (2002).
Greaves, T. S. et al. Follicular lesions of thyroid: a 5-year fine-needle aspiration experience. Cancer 90, 335–341 (2000).
Sclabas, G. M. et al. Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of 240 patients. Am. J. Surg. 186, 702–709 (2003).
Cooper, D. S. et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16, 109–142 (2006).
Yassa, L. et al. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer 111, 508–516 (2007).
Adeniran, A. J. et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am. J. Surg. Pathol. 30, 216–222 (2006).
Kimura, E. T. 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. 63, 1454–1457 (2003).
Soares, P. et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22, 4578–4580 (2003).
Frattini, M. et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene 23, 7436–7440 (2004).
Santoro, M. et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J. Clin. Invest. 89, 1517–1522 (1992).
Jhiang, S. M. et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137, 375–378 (1996).
Santoro, M. et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12, 1821–1826 (1996).
Powell, D. J. Jr et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res. 58, 5523–5528 (1998).
Grieco, M. 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 60, 557–563 (1990).
Santoro, M. et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 9, 509–516 (1994).
Pierotti, M. A. et al. 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 89, 1616–1620 (1992).
Minoletti, F. et al. The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Genes Chromosomes Cancer 11, 51–57 (1994).
Bongarzone, I. et al. 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. 13, 358–366 (1993).
Klugbauer, S., Demidchik, E. P., Lengfelder, E. & Rabes, H. M. 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. 58, 198–203 (1998).
Klugbauer, S. & Rabes, H. M. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 18, 4388–4393 (1999).
Klugbauer, S., Jauch, A., Lengfelder, E., Demidchik, E. & Rabes, H. M. A novel type of RET rearrangement (PTC8) in childhood papillary thyroid carcinomas and characterization of the involved gene (RFG8). Cancer Res. 60, 7028–7032 (2000).
Salassidis, K. et al. 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. 60, 2786–2789 (2000).
Corvi, R., Berger, N., Balczon, R. & Romeo, G. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 19, 4236–4242 (2000).
Saenko, V. et al. Novel tumorigenic rearrangement, Delta rfp/ret, in a papillary thyroid carcinoma from externally irradiated patient. Mutat. Res. 527, 81–90 (2003).
Nakata, T. 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 Cancer 25, 97–103 (1999).
Ciampi, R., Giordano, T. J., Wikenheiser-Brokamp, K., Koenig, R. J. & Nikiforov, Y. E. HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr. Relat. Cancer 14, 445–452 (2007).
Nikiforov, Y. E. RET/PTC rearrangement in thyroid tumors. Endocr. Pathol. 13, 3–16 (2002).
Tallini, G. & Asa, S. L. RET oncogene activation in papillary thyroid carcinoma. Adv. Anat. Pathol. 8, 345–354 (2001).
Unger, K. et al. Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas. J. Clin. Endocrinol. Metab. 89, 4272–4279 (2004).
Zhu, Z., Ciampi, R., Nikiforova, M. N., Gandhi, M. & Nikiforov, Y. E. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J. Clin. Endocrinol. Metab. 91, 3603–3610 (2006).
Santoro, M. et al. Involvement of RET oncogene in human tumours: specificity of RET activation to thyroid tumours. Br. J. Cancer 68, 460–464 (1993).
Tallini, G. 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. 4, 287–294 (1998).
Nikiforova, M. N., Caudill, C. M., Biddinger, P. & Nikiforov, Y. E. Prevalence of RET/PTC rearrangements in Hashimoto's thyroiditis and papillary thyroid carcinomas. Int. J. Surg. Pathol. 10, 15–22 (2002).
Ishizaka, Y. et al. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene 6, 1667–1672 (1991).
Wirtschafter, A. et al. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto's thyroiditis. Laryngoscope 107, 95–100 (1997).
Sheils, O. M., O'Eary, J. J., Uhlmann, V., Lättich, K. & Sweeney, E. C. ret/PTC-1 Activation in Hashimoto Thyroiditis. Int. J. Surg. Pathol. 8, 185–189 (2000).
Elisei, R. et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J. Clin. Endocrinol. Metab. 86, 3211–3216 (2001).
Chiappetta, G. et al. The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J. Clin. Endocrinol. Metab. 87, 364–369 (2002).
Sapio, M. R. et al. High growth rate of benign thyroid nodules bearing RET/PTC rearrangements. J. Clin. Endocrinol. Metab. 96, E916–E919 (2011).
Guerra, A. et al. Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application. Endocr. J. 58, 31–38 (2011).
Radice, P. et al. The human tropomyosin gene involved in the generation of the TRK oncogene maps to chromosome 1q31. Oncogene 6, 2145–2148 (1991).
Greco, A. et al. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene 7, 237–242 (1992).
Miranda, C., Minoletti, F., Greco, A., Sozzi, G. & Pierotti, M. A. Refined localization of the human TPR gene to chromosome 1q25 by in situ hybridization. Genomics 23, 714–715 (1994).
Pierotti, M. A. et al. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 16, 1–14 (1996).
Bongarzone, I. et al. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin. Cancer Res. 4, 223–228 (1998).
Musholt, T. J. et al. Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery 128, 984–993 (2000).
Suarez, H. G. et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 5, 565–570 (1990).
Esapa, C. T., Johnson, S. J., Kendall-Taylor, P., Lennard, T. W. & Harris, P. E. Prevalence of Ras mutations in thyroid neoplasia. Clin. Endocrinol. (Oxf.) 50, 529–535 (1999).
Motoi, N. et al. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol. Res. Pract. 196, 1–7 (2000).
Manenti, G., Pilotti, S., Re, F. C., Della Porta, G. & Pierotti, M. A. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur. J. Cancer 30A, 987–993 (1994).
Namba, H., Rubin, S. A. & Fagin, J. A. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol. Endocrinol. 4, 1474–1479 (1990).
Karga, H. et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J. Clin. Endocrinol. Metab. 73, 832–836 (1991).
Ezzat, S. et al. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Thyroid 6, 409–416 (1996).
Zhu, Z., Gandhi, M., Nikiforova, M. N., Fischer, A. H. & Nikiforov, Y. E. 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. 120, 71–77 (2003).
Fagin, J. A. Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid. Mol. Endocrinol. 16, 903–911 (2002).
Saavedra, H. I. et al. The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. Oncogene 19, 3948–3954 (2000).
Basolo, F. et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid 10, 19–23 (2000).
Garcia-Rostan, G. et al. Ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J. Clin. Oncol. 21, 3226–3235 (2003).
Cohen, Y. et al. BRAF mutation in papillary thyroid carcinoma. J. Natl Cancer Inst. 95, 625–627 (2003).
Trovisco, V. et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J. Pathol. 202, 247–251 (2004).
Carta, C. 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 (BRAF(V599lns)). Clin. Endocrinol. (Oxf.) 64, 105–109 (2006).
Hou, P., Liu, D. & Xing, M. Functional characterization of the T1799–1801del and A1799–1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle 6, 377–379 (2007).
Chiosea, S. et al. A novel complex BRAF mutation detected in a solid variant of papillary thyroid carcinoma. Endocr. Pathol. 20, 122–126 (2009).
Basolo, F. et al. 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. 95, 4197–4205 (2010).
Ciampi, R. et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Invest. 115, 94–101 (2005).
Xing, M. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 12, 245–262 (2005).
Namba, H. et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab. 88, 4393–4397 (2003).
Nikiforova, M. N. et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J. Clin. Endocrinol. Metab. 88, 5399–5404 (2003).
Begum, S. et al. BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod. Pathol. 17, 1359–1363 (2004).
Ricarte-Filho, J. C. et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 69, 4885–4893 (2009).
Kroll, T. G. et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289, 1357–1360 (2000).
Gregory Powell, J. et al. The PAX8/PPARgamma fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARgamma inhibition. Oncogene 23, 3634–3641 (2004).
French, C. A. et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am. J. Pathol. 162, 1053–1060 (2003).
Nikiforova, M. N. et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J. Clin. Endocrinol. Metab. 88, 2318–2326 (2003).
Dwight, T. et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 88, 4440–4445 (2003).
Nikiforova, M. N., Biddinger, P. W., Caudill, C. M., Kroll, T. G. & Nikiforov, Y. E. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am. J. Surg. Pathol. 26, 1016–1023 (2002).
Marques, A. R. et al. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J. Clin. Endocrinol. Metab. 87, 3947–3952 (2002).
Castro, P. et al. PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 91, 213–220 (2006).
Fagin, J. A. et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J. Clin. Invest. 91, 179–184 (1993).
Donghi, R. et al. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J. Clin. Invest. 91, 1753–1760 (1993).
Dobashi, Y. et al. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagn. Mol. Pathol. 3, 9–14 (1994).
Ito, T. et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res. 52, 1369–1371 (1992).
Garcia-Rostan, G. 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. 158, 987–996 (2001).
Garcia-Rostan, G. et al. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res. 59, 1811–1815 (1999).
Kurihara, T. et al. Immunohistochemical and sequencing analyses of the Wnt signaling components in Japanese anaplastic thyroid cancers. Thyroid 14, 1020–1029 (2004).
García-Rostán, G. et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 65, 10199–10207 (2005).
Santarpia, L., El-Naggar, A. K., Cote, G. J., Myers, J. N. & Sherman, S. I. Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 93, 278–284 (2008).
Hou, P. et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin. Cancer Res. 13, 1161–1170 (2007).
Dahia, P. L. et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 57, 4710–4713 (1997).
Bonora, E., Evangelisti, C., Bonichon, F., Tallini, G. & Romeo, G. Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas. Br. J. Cancer 95, 1529–1536 (2006).
Máximo, V. & Sobrinho-Simões, M. Hurthle cell tumours of the thyroid. A review with emphasis on mitochondrial abnormalities with clinical relevance. Virchows Arch. 437, 107–115 (2000).
Tallini, G. Oncocytic tumours. Virchows Arch. 433, 5–12 (1998).
Katoh, R., Harach, H. R. & Williams, E. D. Solitary, multiple, and familial oxyphil tumours of the thyroid gland. J. Pathol. 186, 292–299 (1998).
Máximo, V. 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 92, 1892–1898 (2005).
Angell, J. E., Lindner, D. J., Shapiro, P. S., Hofmann, E. R. & Kalvakolanu, D. V. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J. Biol. Chem. 275, 33416–33426 (2000).
Gasparre, G. et al. Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors. Proc. Natl Acad. Sci. USA 104, 9001–9006 (2007).
Máximo, V., Soares, P., Lima, J., Cameselle-Teijeiro, J. & Sobrinho-Simões, M. Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors. Am. J. Pathol. 160, 1857–1865 (2002).
Bonora, E. et al. Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res. 66, 6087–6096 (2006).
Giordano, T. J. et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 24, 6646–6656 (2005).
Chevillard, S. et al. Gene expression profiling of differentiated thyroid neoplasms: diagnostic and clinical implications. Clin. Cancer Res. 10, 6586–6597 (2004).
Huang, Y. et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc. Natl Acad. Sci. USA 98, 15044–15049 (2001).
Mazzanti, C. et al. Using gene expression profiling to differentiate benign versus malignant thyroid tumors. Cancer Res. 64, 2898–2903 (2004).
Lubitz, C. C. & Fahey, T. J. 3rd. The differentiation of benign and malignant thyroid nodules. Adv. Surg. 39, 355–377 (2005).
Prasad, N. B. et al. Identification of genes differentially expressed in benign versus malignant thyroid tumors. Clin. Cancer Res. 14, 3327–3337 (2008).
Finley, D. J., Arora, N., Zhu, B., Gallagher, L. & Fahey, T. J. 3rd. Molecular profiling distinguishes papillary carcinoma from benign thyroid nodules. J. Clin. Endocrinol. Metab. 89, 3214–3223 (2004).
Knauf, J. A. et al. Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFbeta signaling. Oncogene 30, 3153–3162 (2011).
Vasko, V. et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc. Natl Acad. Sci. USA 104, 2803–2808 (2007).
Chen, Y. T., Kitabayashi, N., Zhou, X. K., Fahey, T. J. 3rd & Scognamiglio, T. MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma. Mod. Pathol. 21, 1139–1146 (2008).
He, H. et al. The role of microRNA genes in papillary thyroid carcinoma. Proc. Natl Acad. Sci. USA 102, 19075–19080 (2005).
Nikiforova, M. N., Chiosea, S. I. & Nikiforov, Y. E. MicroRNA expression profiles in thyroid tumors. Endocr. Pathol. 20, 85–91 (2009).
Pallante, P. et al. MicroRNA deregulation in human thyroid papillary carcinomas. Endocr. Relat. Cancer 13, 497–508 (2006).
Nikiforova, M. N., Tseng, G. C., Steward, D., Diorio, D. & Nikiforov, Y. E. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J. Clin. Endocrinol. Metab. 93, 1600–1608 (2008).
Visone, R. et al. MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr. Relat. Cancer 14, 791–798 (2007).
Jazdzewski, K. et al. Thyroid hormone receptor beta (THRB) is a major target gene for microRNAs deregulated in papillary thyroid carcinoma (PTC). J. Clin. Endocrinol. Metab. 96, E546–E553 (2011).
Weber, F., Teresi, R. E., Broelsch, C. E., Frilling, A. & Eng, C. A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma. J. Clin. Endocrinol. Metab. 91, 3584–3591 (2006).
Visone, R. et al. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 26, 7590–7595 (2007).
Xing, M. Gene methylation in thyroid tumorigenesis. Endocrinology 148, 948–953 (2007).
Zuo, H. et al. Downregulation of Rap1GAP through epigenetic silencing and loss of heterozygosity promotes invasion and progression of thyroid tumors. Cancer Res. 70, 1389–1397 (2010).
Russo, D., Damante, G., Puxeddu, E., Durante, C. & Filetti, S. Epigenetics of thyroid cancer and novel therapeutic targets. J. Mol. Endocrinol. 46, R73–R81 (2011).
Hu, S. et al. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int. J. Cancer 119, 2322–2329 (2006).
Rabes, H. M. et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin. Cancer Res. 6, 1093–1103 (2000).
Nikiforov, Y. E., Rowland, J. M., Bove, K. E., Monforte-Munoz, H. & Fagin, J. A. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 57, 1690–1694 (1997).
Bounacer, A. et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 15, 1263–1273 (1997).
Smida, J. et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int. J. Cancer 80, 32–38 (1999).
Nikiforova, M. N. et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett. 209, 1–6 (2004).
Hamatani, K. et al. RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. Cancer Res. 68, 7176–7182 (2008).
Takahashi, K. et al. The presence of BRAF point mutation in adult papillary thyroid carcinomas from atomic bomb survivors correlates with radiation dose. Mol. Carcinog. 46, 242–248 (2007).
Ito, T. et al. In vitro irradiation is able to cause RET oncogene rearrangement. Cancer Res. 53, 2940–2943 (1993).
Caudill, C. M., Zhu, Z., Ciampi, R., Stringer, J. R. & Nikiforov, Y. E. Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation. J. Clin. Endocrinol. Metab. 90, 2364–2369 (2005).
Mizuno, T., Kyoizumi, S., Suzuki, T., Iwamoto, K. S. & Seyama, T. Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. Oncogene 15, 1455–1460 (1997).
Mizuno, T. et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 19, 438–443 (2000).
Nikiforova, M. N. et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290, 138–141 (2000).
Gandhi, M., Medvedovic, M., Stringer, J. R. & Nikiforov, Y. E. Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements. Oncogene 25, 2360–2366 (2006).
Roccato, E. et al. Proximity of TPR and NTRK1 rearranging loci in human thyrocytes. Cancer Res. 65, 2572–2576 (2005).
Büttel, I., Fechter, A. & Schwab, M. Common fragile sites and cancer: targeted cloning by insertional mutagenesis. Ann. NY Acad. Sci. 1028, 14–27 (2004).
Richards, R. I. Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet. 17, 339–345 (2001).
Gandhi, M., Dillon, L. W., Pramanik, S., Nikiforov, Y. E. & Wang, Y. H. DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells. Oncogene 29, 2272–2280 (2010).
Fenton, C. L. et al. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J. Clin. Endocrinol. Metab. 85, 1170–1175 (2000).
Guan, H. et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J. Clin. Endocrinol. Metab. 94, 1612–1617 (2009).
Lind, P. et al. Epidemiology of thyroid diseases in iodine sufficiency. Thyroid 8, 1179–1183 (1998).
Pellegriti, G. et al. Papillary thyroid cancer incidence in the volcanic area of Sicily. J. Natl Cancer Inst. 101, 1575–1583 (2009).
Parkin, D. M., Bray, F., Ferlay, J. & Pisani, P. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108 (2005).
Baloch, Z. W., Fleisher, S., LiVolsi, V. A. & Gupta, P. K. Diagnosis of “follicular neoplasm”: a gray zone in thyroid fine-needle aspiration cytology. Diagn. Cytopathol. 26, 41–44 (2002).
Mazzaferri, E. L. Management of a solitary thyroid nodule. N. Engl. J. Med. 328, 553–559 (1993).
Baloch, Z. W. et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn. Cytopathol. 36, 425–437 (2008).
Nikiforova, M. N. & Nikiforov, Y. E. Molecular diagnostics and predictors in thyroid cancer. Thyroid 19, 1351–1361 (2009).
Kim, S. K. et al. Surgical results of thyroid nodules according to a management guideline based on the BRAF(V600E) mutation status. J. Clin. Endocrinol. Metab. 96, 658–664 (2011).
Kim, S. W. et al. BRAFV600E mutation analysis in fine-needle aspiration cytology specimens for evaluation of thyroid nodule: a large series in a BRAFV600E-prevalent population. J. Clin. Endocrinol. Metab. 95, 3693–3700 (2010).
Nam, S. Y. et al. BRAF V600E mutation analysis of thyroid nodules needle aspirates in relation to their ultrasongraphic classification: a potential guide for selection of samples for molecular analysis. Thyroid 20, 273–279 (2010).
Nikiforov, Y. E. et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J. Clin. Endocrinol. Metab. 94, 2092–2098 (2009).
Pizzolanti, G. et al. Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. Thyroid 17, 1109–1115 (2007).
Jo, Y. S. et al. Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas. Clin. Endocrinol. (Oxf.) 70, 139–144 (2009).
Cohen, Y. 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. 10, 2761–2765 (2004).
Salvatore, G. et al. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 89, 5175–5180 (2004).
Kim, S. K. et al. Pyrosequencing analysis for detection of a BRAFV600E mutation in an FNAB specimen of thyroid nodules. Diagn. Mol. Pathol. 17, 118–125 (2008).
Cantara, S. et al. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J. Clin. Endocrinol. Metab. 95, 1365–1369 (2010).
Ohori, N. P. et al. Contribution of molecular testing to thyroid fine-needle aspiration cytology of “follicular lesion of undetermined significance/atypia of undetermined significance”. Cancer Cytopathol. 118, 17–23 (2010).
Moses, W. et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J. Surg. 34, 2589–2594 (2010).
Cyniak-Magierska, A., Wojciechowska-Durczynska, K., Krawczyk-Rusiecka, K., Zygmunt, A. & Lewinski, A. Assessment of RET/PTC1 and RET/PTC3 rearrangements in fine-needle aspiration biopsy specimens collected from patients with Hashimoto's thyroiditis. Thyroid Res. 4, 5 (2011).
Ali, S. Z. & Cibas, E. S. (Eds) The Bethesda System for Reporting Thyroid Cytopathology (Springer, New York, 2010).
Cooper, D. S. et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–1214 (2009).
Xing, M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr. Rev. 28, 742–762 (2007).
Xing, M. et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J. Clin. Endocrinol. Metab. 90, 6373–6379 (2005).
Kim, T. Y. et al. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin. Endocrinol. (Oxf.) 65, 364–368 (2006).
Kebebew, E. et al. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann. Surg. 246, 466–470 (2007).
Xing, M. et al. BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. J. Clin. Oncol. 27, 2977–2982 (2009).
Elisei, R. et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J. Clin. Endocrinol. Metab. 93, 3943–3949 (2008).
O'Neill, C. J. et al. BRAF(V600E) mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer. Surgery 148, 1139–1145 (2010).
Yip, L. et al. Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 146, 1215–1223 (2009).
Riesco-Eizaguirre, G., Gutiérrez-Martínez, P., García-Cabezas, M. A., Nistal, M. & Santisteban, P. The oncogene BRAF V600E 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. Endocr. Relat. Cancer 13, 257–269 (2006).
Durante, C. et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J. Clin. Endocrinol. Metab. 92, 2840–2843 (2007).
Xing, M. Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol. Cell. Endocrinol. 321, 86–93 (2010).
Rodolico, V. et al. BRAF V600E mutation and p27 kip1 expression in papillary carcinomas of the thyroid ≤1 cm and their paired lymph node metastases. Cancer 110, 1218–1226 (2007).
Lee, X. et al. Analysis of differential BRAF(V600E) mutational status in high aggressive papillary thyroid microcarcinoma. Ann. Surg. Oncol. 16, 240–245 (2009).
Lupi, C. et al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 92, 4085–4090 (2007).
Frasca, F. et al. BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocr. Relat. Cancer 15, 191–205 (2008).
Kwak, J. Y. et al. Association of BRAFV600E mutation with poor clinical prognostic factors and US features in Korean patients with papillary thyroid microcarcinoma. Radiology 253, 854–860 (2009).
Lin, K. L. et al. The BRAF mutation is predictive of aggressive clinicopathological characteristics in papillary thyroid microcarcinoma. Ann. Surg. Oncol. 17, 3294–3300 (2010).
Soares, P. & Sobrinho-Simões, M. Cancer: Small papillary thyroid cancers—is BRAF of prognostic value? Nat. Rev. Endocrinol. 7, 9–10 (2011).
Howell, G. M. et al. Both BRAF V600E mutation and older age (≥65 years) are associated with recurrent papillary thyroid cancer. Ann. Surg. Oncol. doi: 10.1245/s10434-011-1781-5.
Niemeier, L. A. et al. A combined molecular-pathological score improves risk stratification of thyroid papillary microcarcinoma. Cancer (in press).
Belge, G. et al. Upregulation of HMGA2 in thyroid carcinomas: a novel molecular marker to distinguish between benign and malignant follicular neoplasias. Genes Chromosomes Cancer 47, 656–663 (2008).
Chiappetta, G. et al. HMGA2 mRNA expression correlates with the malignant phenotype in human thyroid neoplasias. Eur. J. Cancer 44, 1015–1021 (2008).
Lappinga, P. J. et al. HMGA2 gene expression analysis performed on cytologic smears to distinguish benign from malignant thyroid nodules. Cancer Cytopathol. 118, 287–297 (2010).
Mathur, A. et al. A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy. Surgery 148, 1170–1176 (2010).
Chudova, D. et al. Molecular classification of thyroid nodules using high-dimensionality genomic data. J. Clin. Endocrinol. Metab. 95, 5296–5304 (2010).
Mazeh, H. et al. Development of a microRNA-based molecular assay for the detection of papillary thyroid carcinoma in aspiration biopsy samples. Thyroid 21, 111–118 (2011).
Yip, L. et al. MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann. Surg. Oncol. 18, 2035–2041 (2011).
Chou, C. K. et al. miR-146b is highly expressed in adult papillary thyroid carcinomas with high risk features including extrathyroidal invasion and the BRAF(V600E) mutation. Thyroid 20, 489–494 (2010).
This work was supported by the NIH grant CA88041.
The authors declare no competing financial interests.
About this article
Cite this article
Nikiforov, Y., Nikiforova, M. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 7, 569–580 (2011). https://doi.org/10.1038/nrendo.2011.142
SGSM2 inhibits thyroid cancer progression by activating RAP1 and enhancing competitive RAS inhibition
Cell Death & Disease (2022)
Indian Journal of Otolaryngology and Head & Neck Surgery (2022)
An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks
Molecular Cancer (2021)
World Journal of Surgical Oncology (2021)