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64 - Oncogenic events and therapeutic targets in thyroid cancer

from Part 3.4 - Molecular pathology: endocrine cancers

Published online by Cambridge University Press:  05 February 2015

By
James A. Fagin  and
Julio C. Ricarte Filho
Edited by
Edward P. Gelmann ,
Charles L. Sawyers  and
Frank J. Rauscher, III
James A. Fagin
Affiliation:
Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Julio C. Ricarte Filho
Affiliation:
Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY,USA
Edward P. Gelmann
Affiliation:
Columbia University, New York
Charles L. Sawyers
Affiliation:
Memorial Sloan-Kettering Cancer Center, New York
Frank J. Rauscher, III
Affiliation:
The Wistar Institute Cancer Centre, Philadelphia
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Summary

The thyroid contains two endocrine cell types: follicular cells, which secrete thyroid hormones, and parafollicular or C cells, the primary source of calcitonin. Most of this chapter is dedicated to reviewing the molecular and phenotypic characteristics of cancers derived from follicular cells, as they represent about 95% of all cancers arising from this gland, focusing in particular on oncoproteins that represent potential therapeutic targets for the disease.

The oncogenic repertoire of thyroid cancers of follicular cells

There are two major histological types of differentiated thyroid cancer: papillary (PTC) and follicular (FTC; Figure 64.1). PTCs arise as sporadic tumors, with a female preponderance, and are the most common form of the disease. Several key genetic events involved in PTC pathogenesis have been identified. Mutations of the receptor tyrosine kinases (RTK) RET or TRK, of the three RAS genes (NRAS>HRAS>KRAS), or of BRAF account for about 70% of these tumors. With very rare exceptions mutations in these genes is mutually exclusive in thyroid carcinomas of all stages of differentiation, suggesting that just one activating event in the RTK-Ras-Raf-MEK-ERK pathway is sufficient to drive tumorigenesis (1).

Type
Chapter
Information
Molecular Oncology
Causes of Cancer and Targets for Treatment
 , pp. 704 - 711
Publisher: Cambridge University Press
Print publication year: 2013

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References

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 Research 2003;63:1454–7.Google ScholarPubMed
Santoro, M, Melillo, RM, Carlomagno, F, Fusco, A, Vecchio, G.Molecular mechanisms of RET activation in human cancer. Annals of the New York Academy of Science 2002;963:116–21.CrossRefGoogle ScholarPubMed
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 Research 1997;57:1690–4.Google ScholarPubMed
Thomas, GA, Bunnell, H, Cook, HA, et al. High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. Journal of Clinical Endocrinology and Metabolism 1999;84:4232–8.Google ScholarPubMed
Mizuno, T, Iwamoto, KS, Kyoizumi, S, et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 2000;19:438–43.CrossRefGoogle ScholarPubMed
Caudill, CM, Zhu, Z, Ciampi, R, Stringer, JR, Nikiforov, YE.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. Journal of Clinical Endocrinology and Metabolism 2005;90:2364–9.CrossRefGoogle ScholarPubMed
Powell, DJ, Jr., Russell, J, Nibu, K, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Research 1998;58:5523–8.Google ScholarPubMed
Jhiang, SM, Sagartz, JE, Tong, Q, et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 1996;137:375–8.CrossRefGoogle ScholarPubMed
Bongarzone, I, Vigneri, P, Mariani, L, et al. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clinical Cancer Research 1998;4:223–8.Google ScholarPubMed
Pierotti, MA, Bongarzone, I, Borello, MG, et al. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes, Chromosomes and Cancer 1996;16:1–14.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Greco, A, Fusetti, L, Miranda, C, et al. Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene. Oncogene 1998;16:809–16.CrossRefGoogle ScholarPubMed
Roccato, E, Bressan, P, Sabatella, G, et al. Proximity of TPR and NTRK1 rearranging loci in human thyrocytes. Cancer Research 2005;65:2572–6.CrossRefGoogle ScholarPubMed
Nikiforova, MN, Stringer, JR, Blough, R, et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 2000;290:138–41.CrossRefGoogle ScholarPubMed
. Accessed August 2008.
Vasko, V, Ferrand, M, Di Cristofaro, J, et al. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. Journal of Clinical Endocrinology and Metabolism 2003;88:2745–52.CrossRefGoogle ScholarPubMed
Zhu, Z, Gandhi, M, Nikiforova, MN, Fischer, AH, Nikiforov, YE.Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma: an unusually high prevalence of ras mutations. American Journal of Clinical Pathology 2003;120:71–7.CrossRefGoogle ScholarPubMed
Adeniran, AJ, Zhu, Z, Gandhi, M, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. American Journal of Surgical Pathology 2006;30:216–22.CrossRefGoogle ScholarPubMed
Hara, H, Fulton, N, Yashiro, T, et al. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery 1994;116:1010–16.Google ScholarPubMed
Namba, H, Rubin, SA, Fagin, JA.Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Molecular Endocrinology 1990;4:1474–9.CrossRefGoogle ScholarPubMed
Chen, X, Mitsutake, N, LaPerle, K, et al. Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene. Proceedings of the National Academy of Sciences USA 2009;106:7979–84.CrossRefGoogle ScholarPubMed
Miller, KA, Yeager, N, Baker, K, et al. Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Research 2009;69:3689–94.CrossRefGoogle ScholarPubMed
Vitagliano, D, Portella, G, Troncone, G, et al. Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas. Oncogene 2006;25:5467–74.CrossRefGoogle ScholarPubMed
Kroll, TG, Sarraf, P, Pecciarini, L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289:1357–60.CrossRefGoogle Scholar
Lui, WO, Zeng, L, Rehrmann, V, et al. CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Research 2008;68:7156–64.CrossRefGoogle ScholarPubMed
Eberhardt, NL, Grebe, SK, McIver, B, Reddi, HV.The role of the PAX8/PPARgamma fusion oncogene in the pathogenesis of follicular thyroid cancer. Molecular and Cellular Endocrinology 2010;321:50–6.CrossRefGoogle ScholarPubMed
Diallo-Krou, E, Yu, J, Colby, LA, et al. Paired box gene 8-peroxisome proliferator-activated receptor-gamma fusion protein and loss of phosphatase and tensin homolog synergistically cause thyroid hyperplasia in transgenic mice. Endocrinology 2009;150:5181–90.CrossRefGoogle ScholarPubMed
Soares, P, Trovisco, V, Rocha, AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003;22:4578–80.CrossRefGoogle ScholarPubMed
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 Research 2003;63:4561–7.Google ScholarPubMed
Cohen, Y, Xing, M, Mambo, E, et al. BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute 2003;95:625–7.CrossRefGoogle ScholarPubMed
Nikiforova, MN, Kimura, ET, Gandhi, M, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. Journal of Clinical Endocrinology and Metabolism 2003;88:5399–404.CrossRefGoogle ScholarPubMed
Sedliarou, I, Saenko, V, Lantsov, D, et al. The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. International Journal of Oncology 2004;25:1729–35.Google ScholarPubMed
Ciampi, R, Knauf, JA, Kerler, R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. Journal of Clinical Investigation 2005;115:94–101.CrossRefGoogle ScholarPubMed
Mesa, C, Jr., Mirza, M, Mitsutake, N, et al. Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Research 2006;66:6521–9.CrossRefGoogle ScholarPubMed
Xing, M.BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocrine Reviews 2007;28:742–62.CrossRefGoogle ScholarPubMed
Xing, M, Westra, WH, Tufano, RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2005;90:6373–9.CrossRefGoogle ScholarPubMed
Elisei, R, Ugolini, C, Viola, D, et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. Journal of Clinical Endocrinology and Metabolism 2008;93:3943–9.CrossRefGoogle ScholarPubMed
Giordano, TJ, Kuick, R, Thomas, DG, 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 2005;24:6646–56.CrossRefGoogle ScholarPubMed
Franco, AT, Malaguarnera, R, Refetoff, S, et al. Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice. Proceedings of the National Academy of Sciences USA 2011;108:1615–20.CrossRefGoogle ScholarPubMed
Boelaert, K, Horacek, J, Holder, RL, et al. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. Journal of Clinical Endocrinology and Metabolism 2006;91:4295–301.CrossRefGoogle ScholarPubMed
Haymart, MR, Repplinger, DJ, Leverson, GE, et al. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. Journal of Clinical Endocrinology and Metabolism 2008;93:809–14.CrossRefGoogle ScholarPubMed
Fiore, E, Rago, T, Provenzale, MA, et al. Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role. Endocrine Related Cancer 2009;16:1251–60.CrossRefGoogle ScholarPubMed
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 Research 2005;65:4238–45.CrossRefGoogle ScholarPubMed
Knauf, JA, Sartor, MA, Medvedovic, M, et al. Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGF-beta signaling. Oncogene 2011;30:3153–62.CrossRefGoogle Scholar
Salvatore, G, De Falco, V, Salerno, P, et al. BRAF is a therapeutic target in aggressive thyroid carcinoma. Clinical Cancer Research 2006;12:1623–9.CrossRefGoogle ScholarPubMed
Mitsiades, CS, Negri, J, McMullan, C, et al. Targeting BRAFV600E in thyroid carcinoma: therapeutic implications. Molecular Cancer Therapeutics 2007;6:1070–8.CrossRefGoogle ScholarPubMed
Sala, E, Mologni, L, Truffa, S, et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Molecular Cancer Research 2008;6:751–9.CrossRefGoogle ScholarPubMed
Salerno, P, De Falco, V, Tamburrino, A, et al. Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells. Journal of Clinical Endocrinology and Metabolism 2010;95:450–5.CrossRefGoogle ScholarPubMed
Ouyang, B, Knauf, JA, Smith, EP, et al. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clinical Cancer Research 2006;12:1785–93.CrossRefGoogle ScholarPubMed
Ball, DW, Jin, N, Rosen, DM, et al. Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. Journal of Clinical Endocrinology and Metabolism 2007;92:4712–18.CrossRefGoogle ScholarPubMed
Rivera, M, Ricarte-Filho, J, Patel, S, et al. Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study. Human Pathology 2010;41:172–80.CrossRefGoogle ScholarPubMed
Liaw, D, Marsh, DJ, Li, J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genetics 1997;16:64–7.CrossRefGoogle ScholarPubMed
Frisk, T, Foukakis, T, Dwight, T, et al. Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer. Genes, Chromosomes and Cancer 2002;35:74–80.CrossRefGoogle ScholarPubMed
Paes, JE, Ringel, MD.Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia. Endocrinology and Metabolism Clinics of North America 2008;37:375–87.CrossRefGoogle ScholarPubMed
Samuels, Y, Diaz, LA, Jr., Schmidt-Kittler, O, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005;7:561–73.CrossRefGoogle ScholarPubMed
Samuels, Y, Wang, Z, Bardelli, A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:11.CrossRefGoogle ScholarPubMed
Garcia-Rostan, G, Costa, AM, Pereira-Castro, I, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Research 2005;65:10 199–207.CrossRefGoogle ScholarPubMed
Hou, P, Liu, D, Shan, Y, et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clinical Cancer Research 2007;13:1161–70.CrossRefGoogle ScholarPubMed
Liu, Z, Hou, P, Ji, M, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. Journal of Clinical Endocrinology and Metabolism 2008;93:3106–16.CrossRefGoogle ScholarPubMed
Abubaker, J, Jehan, Z, Bavi, P, et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. Journal of Clinical Endocrinology and Metabolism 2008;93:611–18.CrossRefGoogle Scholar
Carpten, JD, Faber, AL, Horn, C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439–44.CrossRefGoogle Scholar
Ricarte-Filho, JC, Ryder, M, Chitale, DA, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Research 2009;69:4885–93.CrossRefGoogle ScholarPubMed
Ito, T, Seyama, T, Mizuno, T, et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Research 1992;52:1369–71.Google Scholar
Fagin, JA, Matsuo, K, Karmakar, A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. Journal of Clinical Investigation 1993;91:179–84.CrossRefGoogle ScholarPubMed
Garcia-Rostan, G, Tallini, G, Herrero, A, et al. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Research 1999;59:1811–15.Google ScholarPubMed
Cetta, F, Curia, MC, Montalto, G, et al. Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene. Journal of Clinical Endocrinology and Metabolism 2001;86:427–32.Google ScholarPubMed
Castellone, MD, De Falco, V, Rao, DM, et al. The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation. Cancer Research 2009;69:1867–76.CrossRefGoogle ScholarPubMed
Guigon, CJ, Cheng, SY.Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis. Molecular and Cellular Endocrinology 2009;308:63–9.CrossRefGoogle ScholarPubMed
Gudmundsson, J, Sulem, P, Gudbjartsson, DF, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nature Genetics 2009;41:460–4.CrossRefGoogle ScholarPubMed
Landa, I, Ruiz-Llorente, S, Montero-Conde, C, et al. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS Genetics 2009;5:4.CrossRefGoogle ScholarPubMed
Takahashi, M, Saenko, VA, Rogounovitch, TI, et al. The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Human Molecular Genetics 2010;19:2516–23.CrossRefGoogle ScholarPubMed
Carlomagno, F, Santoro, M.Thyroid cancer in 2010: a roadmap for targeted therapies. Nature Reviews Endocrinology 2011;7:65–7.CrossRefGoogle ScholarPubMed
Fagin, JA, Tuttle, RM, Pfister, DG.Harvesting the low-hanging fruit: kinase inhibitors for therapy of advanced medullary and nonmedullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2010;95:2621–4.CrossRefGoogle ScholarPubMed
Durante, C, Haddy, N, Baudin, E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism 2006;91:2892–9.CrossRefGoogle ScholarPubMed
Knauf, JA, Kuroda, H, Basu, S, Fagin, JA.RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene 2003;22:4406–12.CrossRefGoogle ScholarPubMed
Mitsutake, N, Knauf, JA, Mitsutake, S, et al. Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Research 2005;65:2465–73.CrossRefGoogle ScholarPubMed
Riesco-Eizaguirre, G, Rodriguez, I, De la Vieja, A, et al. The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Research 2009;69:8317–25.CrossRefGoogle ScholarPubMed
Liu, D, Hu, S, Hou, P, et al. Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clinical Cancer Research 2007;13:1341–9.CrossRefGoogle ScholarPubMed
Fagin, JA, Mitsiades, N.Molecular pathology of thyroid cancer: diagnostic and clinical implications. Best Practice and Research in Clinical Endocrinology and Metabolism 2008;22:955–69.CrossRefGoogle ScholarPubMed
Drosten, M, Stiewe, T, Putzer, BM.Antitumor capacity of a dominant-negative RET proto-oncogene mutant in a medullary thyroid carcinoma model. Human Gene Therapy 2003;14:971–82.CrossRefGoogle Scholar
Carlomagno, F, Santoro, M.Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer. Journal of Chemotherapy 2004;4:49–51.CrossRefGoogle Scholar
Wells, SA, Santoro, M.Targeting the RET pathway in thyroid cancer. Clinical Cancer Research 2009;15:7119–23.CrossRefGoogle ScholarPubMed
Akeno-Stuart, N, Croyle, M, Knauf, JA, et al. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Research 2007;67:6956–64.CrossRefGoogle ScholarPubMed
Wells, SA, Gosnell, JE, Gagel, RF, et al. Vandetanib in metastatic hereditary medullary thyroid cancer: follow-up results of an open-label Phase II trial. Journal of Clinical Oncology 2007;25 (suppl.; abstr. 6018).Google Scholar

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