Cover Image

BRAF Mutation and its effects on Radioiodine Uptake in Patients with Anaplastic Thyroid Cancer

Farzaneh Bozorg-Ghalati, Mehdi Hedayati


Context: Anaplastic thyroid carcinoma (ATC) is poorly differentiated subtype of thyroid cancer which either resistant to radioactive iodine (RAI) therapy or conventional chemotherapy. Each process of the biological characteristics in normal thyroid cells, including iodide uptake by sodium-iodide symporter (NIS), synthesis of thyroglobulin (Tg), expression of thyroid peroxidase (TPO) and receptor for thyrotropin (TSHR), can be an onset stage for emerging thyroid carcinoma. Decrease or absence of NIS mRNA in thyroid carcinomas has well described for resistant to RAI therapy in these patients.

Evidence Acquisition: The original articles related to the role of the BRAF mutations on the sodium-iodide symporter functions and radioiodine uptake in patients with anaplastic thyroid carcinoma were found by a search in Scopus, PubMed, Science direct, Springer and some else with an emphasis on literature published in the recent years.

Results: The related studies disclosed that mutations in the mitogen-activated protein kinase (MAPK) pathway happen in more than 90% of thyroid cancer. Also serine/threonine-protein kinase BRAF is an important component of the MAPK pathway. Its mutations cause reduction of NIS mRNA compared to tumors with other mutations.


BRAF mutation; Sodium-iodide symporter; Anaplastic thyroid cancer


Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011, 61(2):69-90

Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013, 2013:1-10

Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013, 13(3):184-199

Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ,et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009, 19(11):1167-1214

Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. 2009, 16(1):17-44

Gervasi R, Orlando G, Lerose MA, Amato B, Docimo G, Zeppa P, et al. Thyroid surgery in geriatric patients: a literature review. BMC Surg. 2012, 12(1):1-16

Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer. 2005, 103(11):2261-2268

Reddi H-V, Kumar A, Kulstad R. Anaplastic thyroid cancer an overview of genetic variations and treatment modalities. Advances in Genomics and Genetics. 2015, 5:43-52

Ragazzi M, Ciarrocchi A, Sancisi V, Gandolfi G, Bisagni A, Piana S. Update on Anaplastic Thyroid Carcinoma: Morphological, Molecular, and Genetic Features of the Most Aggressive Thyroid Cancer. Int J Endocrinol. 2014, 2014:1-13

Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006, 6(4):292-306

Oktay MH, Smolkin MB, Williams M, Cajigas A. Metastatic anaplastic carcinoma of the thyroid mimicking squamous cell carcinoma: report of a case of a challenging cytologic diagnosis. Acta Cytol. 2006, 50(2):201-204

Gunes P, Aker FV, Erkan M, Demirturk P, Dulundu E. Incidental anaplastic thyroid carcinoma: A case report. Turkish J Pathol. 2008, 24(1):54-58

Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid. 2010, 20(2):135-146

Savin S, Cvejic D, Isic T, Paunovic I, Tatic S, Havelka M. The efficacy of the thyroid peroxidase marker for distinguishing follicular thyroid carcinoma from follicular adenoma. Exp Oncol. 2006, 28(1):70-74

Gerard AC, Daumerie C, Mestdagh C, Gohy S, Burbure CD,Costagliola S, et al. Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas. J Clin Endocrinol Metab. 2003, 88(10):4977-4983

Sodré AK, Rubio IG, Galrão AL, Knobel M, Tomimori EK, Alves VA, et al. Association of low sodium-iodide symporter messenger ribonucleic acid expression in malignant thyroid nodules with increased intracellular protein staining. J Clin Endo crinol Metab. 2008, 93(10):4141-4145

Bozorg-Ghalati F, Hedayati M. Relationship between PI3K mutation and sodium-iodide symporter in anaplastic thyroid carcinoma. American J Cancer Science. 2015, 4:63-77

Hinterseher U, Wunderlich A, Roth S, Ramaswamy A, Bartsch DK, Hauptmann S, et al. Expression of hedgehog signaling pathway in anaplastic thyroid cancer. Endocrine. 2014, 45(3):439-447

Guerra A, Crescenzo VD, Garzi A, Mariapia C, Carlomagno C, Tonacchera M, et al. Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic review. BMC Surgery. 2013, 13(2):44-50

Guerra A, Marotta V, Deandrea M, Motta M, Limone PP, Caleo A, et al. BRAF (V600E) associates with cytoplasmic localization of p27kip1 and higher cytokeratin 19 expression in papillary thyroid carcinoma. Endocrine. 2013, 44(1):165-171

Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002, 298(5600):1911-1912

Morrison DK, Davis RJ. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev Biol. 2003, 19:91-118

Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Biol. Cell. 2001, 93(1-2):53-62

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011, 144(5):646-674

Pouysségur J, Volmat V, Lenormand P. Fidelity and spatio-temporal control of MAP kinase (ERKs) signalling. Eur J Biochem Pharmacol. 2002, 64(5-6):755-763

Berridge M J. Module 2, Cell Signalling Pathways. Portland Press Limited. 2012, 84-85

Sharrocks AD. The ETS-domain transcription factor family. Nat Rev Mol Cell Biol. 2001, 2(11):827-837

Roskoski R Jr. RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun. 2010, 399(3):313-317

Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J, Rapp UR. The ins and outs of RAF kinases. Trends Biochem Sci. 1994, 19(11):474-480

Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011, 364(24):2305-2315

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002, 417(6892):949-954

Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013, 3(8):862-869

Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espín E, et al. BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene. 2003, 22:9192-9196

Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013, 19(16):4532-4540

Cho YH, Kim DY, Kim JH, Kim YM, Kim KR, Nam JH, et al. Mutational analysis of KRAS, BRAF, and TP53 genes of ovarian serous carcinomas in Korean women. Yonsei Med. J 2009, 50(2):266-272

Pakneshan S, Salajegheh A, Smith RA, Lam AK. Clinicopathological relevance of BRAF mutations in human cancer. Pathology. 2013, 45(4):346-356

Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011, 29(10):1239-1246

Pelizzo MR, Dobrinja C, Casal Ide E, Zane M, Lora O, Toniato A, et al. The role of BRAF (V600E) mutation as poor prognostic factor for the outcome of patients with intra thyroid papillary thyroid carcinoma. Biomed Pharmacother. 2014, 68(4):413-417

Schulten HJ, Alotibi R, Al-Ahmadi A, Ata M, Karim S, Huwait E, et al. Effect of BRAF mutational status on expression profiles in conventional papillary thyroid carcinomas. BMC Genomics. 2015, 16(1):1-10

Takano T, Ito Y, Hirokawa M, Yoshida H, Miyauchi A.BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas. Br J Cancer. 2007, 96(10):1549-1553

Hall RD, Kudchadkar RR. BRAF Mutations: Signaling, Epidemiology, and Clinical Experience in Multiple Malignancies. Cancer Control. 2014, 21(3):221-230

Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010, 8:67-69

Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004, 116(6):855-867

Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, et al. (V600E) BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA. 2009, 106(11):4519-4524

Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin. Invest. 2005, 115(1):94-101

Ibanez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harbor Perspect Biol. 2013, 5(2):a009134

Hedayati M, Nabipour I, Rezaei-Ghaleh N, Azizi F. Germline RET mutations in exons 10 and 11: an Iranian survey of 57 medullary thyroid carcinoma cases. Med J Malaysia. 2006, 61(5):564-569

Hedayati M, Zarif Yeganeh M, Sheikhol Eslami S, Rezghi Barez Sh, Hoghooghi Rad L, Azizi F. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011, 2011:264248

Majidi M, Haghpanah V, Hedayati M, Khashayar P, Mohajeri-Tehrani MR, Larijani B. A family presenting with multiple endocrine neoplasia type 2B: A case report. J Med Case Rep 2011, 5:587

Zarif Yeganeh M, Sheikholeslami S, Hedayati M. RET Proto Oncogene Mutation Detection and Medullary Thyroid Carcinoma Prevention. Asian Pac J Cancer Prev. 2015, 16 (6):2107-2117

Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, et al. The sodium-iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev. 2003, 24(1):48-77

Porra V, Bernier-Valentin F, Trouttet-Masson S, Berger-Dutrieux N, Peix JL, Perrin A, et al. Characterization and semi-quantitative analyses of pendrin expressed in normal and tumoral human thyroid tissues. J Clin Endocrinol Metab. 2002, 87)4):1700-1707

Lacroix L, Pourcher T, Magnon C, Bellon N, Talbot M, Intraphairot T, et al. Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters. J Clin Endocrinol Metab. 2004, 89(3):1423-1428

Wapnir IL, van de Rijn M, Nowels K, Amenta PS, Walton K, Montgomery K. Immunohistochemical profile of the sodium-iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections. J Clin Endocrinol Metab. 2003, 88:1880-1888

Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics. Pharmacol Ther. 2012, 135(3):355-370

Riesco-Eizaguirre G, Santisteban P. A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol. 2006, 155(4):495-512

Zarnegar R, Brunaud L, Kanauchi H, Wong M, Fung M, Ginzinger D, et al. Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A, a histone deacetylase inhibitor. Surgery. 2002, 132(6):984-990

Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006, 91(8):2892-2899

Trouttet-Masson S, Selmi-Ruby S, Bernier-Valentin F, Porra V, Berger-Dutrieux N, Decaussin M, et al. Evidence for transcriptional and posttranscriptional alterations of the sodium-iodide symporter expression in hypo functioning benign and malignant thyroid tumors. AmJ Pathol. 2004, 165(1):25-34

Romei C, Ciampi R, Faviana P, Agate L, Molinaro E, Bottici V, et al. BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocr. Relat. Cancer. 2008, 15(2):511-520

Espadinha C, Santos JR, Sobrinho LG, Bugalho MJ.Expression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependency. Clin Endocrinol (Oxf). 2009, 70(4):629-635

Zhang Z, Liu D, Murugan AK, Liu Z, Xing M. Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer. Endocr Relat Cancer. 2014, 21:161-173

Mitsutake N, Miyagishi M, Mitsutake S, Akeno N, Mesa C, Knauf JA. BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/ PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Endocrinol. 2006, 147(2):1014-1019

Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M, et al. The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. 2009, 69(21):8317-8325

Galrao AL, Sodre AK, Camargo RY, Friguglietti CU, Kulcsar MA, Lima EU. Methylation levels of sodium-iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression. Endocrine. 2013, 43(1):225-229

Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006, 38(7):787-793

Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, et al. DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis. 2006, 27(6):1160-1168

Choi YW, Kim HJ, Kim YH, Park SH, Chwae YJ, Lee J, et al. BRAFV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1. Exp Mol Med. 2014, 46(11):1-10

Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia- Cabezas MA, 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. 2006, 13(1):257-269

Barollo S, Pennelli G, Vianello F, Watutantrige Fernando S, Negro I, Merante Boschin I, et al. BRAF in primary and recurrent papillary thyroid cancers: the relationship with 131I and 2-[18F]fluoro- 2-deoxy-D-glucose uptake ability. Eur J Endocrinol. 2010, 163:659-663

Coelho SM, Carvalho DP, Vaisman M. New Perspectives on the Treatment of Differentiated Thyroid Cancer. Arq Bras Endocrinol Metab. 2007, 51(4):612-624

Brose MS, Smit J, Capdevila J, Elisei R, Nutting C, Pitoia F, et al. Regional approaches to the management of patients with advanced, radioactive iodine- refractory differentiated thyroid carcinoma. Expert Rev Anticancer Ther. 2012, 12(9):1137-1147

Tonacchera M, Viacava P, Agretti P, De Marco G, Perri A, Di Cosmo C, et al. Benign nonfunctioning thyroid adenomas are characterized by a defective targeting to cell membrane or a reduced expression of the sodium iodide symporter protein. J Clin Endocrinol Metab. 2002, 87(1):352-357

Xing M, Alzaharani AS, Carson KA, Viola D, Elisei R, Bendlova B, et al. The BRAF V600E Mutation Increases Mortality in Papillary Thyroid Cancer. Clin Thyroidol. 2013, 25:105-106

Sabra MM, Dominguez JM, Grewal RK, Larson SM, Ghossein RA, Tuttle RM, et al. Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases. J Clin Endocrinol Metab. 2013, 98(5):829-836

Nehs MA, Nucera C, Nagarkatti SS, Sadow PM, Morales-Garcia D, Hodin RA, et al. Late intervention with anti-BRAF (V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer. Endocrinol. 2012, 153(2):985-994

Fagin JA. How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer therapy. J Endocrinol. 2004, 183(2):249-256

Rosove MH, Peddi PF, Glaspy JA. BRAF V600E inhibition in anaplastic thyroid cancer. N Engl J Med. 2013, 368(7):684-685

Kandil E, Tsumagari K, Ma J, Abd Elmageed ZY, Li X, Slakey D, et al. Synergistic inhibition of thyroid cancer by suppressing MAPK/PI3K/AKT pathways. J Surg Res. 2013, 184(2):898-906

Holmlund JT. Applying antisense technology affinitak and other antisense oligonucleotides in clinical development. Ann N Y Acad Sci. 2003, 1002(1):244-251

Kitazono M, Robey R, Zhan Z. Low concentration of the histona deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na+/I- symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab. 2001, 86(7):3430-3435

Catalano MG, Fortunati N, Pugliese M, Costantino L, Poli R, Bosco O, et al. Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab. 2005, 90(3):1383-1389

Jeong H, Kim YR, Kim KN, Choe JG, Chung JK, Kim MK. Effect of all-trans retinoic acid on sodium-iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006, 33(7):875-882

Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind,phase 3 trial. Lancet. 2014, 384(9940):319-328

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011, 364(26):2507-2516

Xing J, Liu R, Xing M, Trink B.The BRAFT1799A mutation confers sensi¬tivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204). Biochem Biophys Res Commun. 2011, 404(4):958-962

Liu D, Hu S, Hou P, Jiang D, Condouris S, Xing M. Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res 2007, 13(4):1341-1349.

Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinasekinase½ kinases: mechanism of action in vivo, harmacokinetic/pharmacodynamics relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007, 6(8):2209-2219

Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013, 368(7):623-632

Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008, 14(1):230-239

Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signaling in colorectal cancer cell lines. Int J Cancer. 2009, 125:2332-2341

Full Text: PDF


  • There are currently no refbacks.

AJCS(ISSN 2572-5750)Copyright © 2012-2017. All rights reserved. Published by Ivy Union Publishing, 3204 Valley Rush Dr, Apex, North Carolina 27502, United States