BRAF mutations in papillary thyroid carcinoma and emerging targeted therapies (Review)

Molecular Medicine Reports

Volumn 6, Issue 4, 2012, Pages 687-694

  Leonardi, Giulia Costanza ^a   Candido, Saverio ^a   Carbone, Maurizio ^b   Raiti, Fabio ^a   Colaianni, Valeria ^b   Garozzo, Sebastiano ^b   Cinà, Diana ^b   McCubrey, James A ^c   Libra, Massimo ^a  

^a UNIVERSITY OF CATANIA   (Italy)

^b GARIBALDI HOSPITAL   (Italy)

^c EAST CAROLINA UNIVERSITY   (United States)

Author keywords

BRAF mutations; Targeted therapies; Thyroid cancer; V600E

Indexed keywords

B RAF KINASE; DEATH ASSOCIATED PROTEIN KINASE; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; N [3 (5 CHLORO 1H PYRROLO[2,3 B]PYRIDINE 3 CARBONYL) 2,4 DIFLUOROPHENYL]PROPANESULFONAMIDE; PENDRIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; RADIOACTIVE IODINE; RAF PROTEIN; RAS PROTEIN; RETINOIC ACID RECEPTOR BETA; SODIUM GLUCOSE COTRANSPORTER 1; THYROGLOBULIN; THYROID PEROXIDASE; TISSUE INHIBITOR OF METALLOPROTEINASE 3; VALINE; VASCULOTROPIN; VEMURAFENIB;

ABLATION THERAPY; AMINO ACID SUBSTITUTION; CANCER GROWTH; CANCER INHIBITION; CANCER INVASION; CANCER RADIOTHERAPY; CANCER RECURRENCE; CANCER STAGING; CARCINOGENESIS; CELL PROLIFERATION; CHROMOSOME 7; DNA METHYLATION; EXTERNAL BEAM RADIOTHERAPY; GENE EXPRESSION; GENE MUTATION; HUMAN; IN VIVO STUDY; MICROARRAY ANALYSIS; MOLECULARLY TARGETED THERAPY; NONHUMAN; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; RADIATION EXPOSURE; REVIEW; SIGNAL TRANSDUCTION; THYROID CARCINOMA; THYROID GLAND; THYROIDECTOMY; TUMOR GROWTH; TUMOR XENOGRAFT;

CARCINOMA; HUMANS; MITOGEN-ACTIVATED PROTEIN KINASES; MUTATION; PROTO-ONCOGENE PROTEINS B-RAF; RECURRENCE; SIGNAL TRANSDUCTION; THYROID NEOPLASMS;

EID: 84865187794     PISSN: 17912997     EISSN: 17913004     Source Type: Journal    
DOI: 10.3892/mmr.2012.1016     Document Type: Review

References (135)

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 59: 225-249, 2009.
2. Davies L and Welch HG: Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295: 2164-2167, 2006.
3. Leenhardt L, Grosclaude P and Cherie-Challine L: Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid 14: 1056-1060, 2004. (Pubitemid 40076130)
4. Williams ED, Abrosimov A, Bogdanova T, Demidchik EP, Ito M, LiVolsi V, Lushnikov E, Rosai J, Tronko MD, Tsyb AF, Vowler SL and Thomas GA: Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake. Thyroid 18: 847-852, 2008.
5. Hunt JL: Radiation induced thyroid diseases. Pathol Case Rev 14: 224-230, 2009.
6. Nakachi K, Hayashi T, Hamatani K, Eguchi H and Kusunoki Y: Sixty years of follow-up of Hiroshima and Nagasaki survivors: cancer progress in molecular epidemiology studies. Mutat Res 659: 109-117, 2008.
7. Williams D: Radiation carcinogenesis: lessons from Chernobyl. Oncogene 27: 9-18, 2009.
8. Sherman SI, Angelos P, Ball DW, Beenken SW, Byrd D, Clark OH, Daniels GH, Dilawari RA, Ehya H, Farrar WB, et al: Thyroid carcinoma. J Natl Compr Canc Netw 3: 404-457, 2005.
9. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI and Tuttle RM: Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16: 109-142, 2006.
10. Mazzaferri EL: Long-term outcome of patients with differentiated thyroid carcinoma: effect of therapy. Endocr Pract 6: 469-476, 2000.
11. Mazzaferri EL and Kloos RT: Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 86: 1447-1463, 2001. (Pubitemid 32374886)
12. Tanaka K, Sonoo H, Hirono M, Ohkubo S, Nomura T, Ikeda M, Nakajima K and Kurebayashi J: Retrospective analysis of predictive factors for recurrence after curatively resected papillary thyroid carcinoma. Surg Today 35: 714-719, 2005. (Pubitemid 41191398)
13. Chan JK: Papillary carcinoma of thyroid: classical and variants. Histol Histopathol 5: 241-257, 1990.
14. Lang BH, Lo CY, Chan WF, Lam AK and Wan KY: Classical and follicular variant of papillary thyroid carcinoma: a comparative study on clinicopathologic features and long-term outcome. World J Surg 30: 752-758, 2006. (Pubitemid 43724102)
15. Keelawat S and Poumsuk U: Association between different variants of papillary thyroid carcinoma and risk-group according to AMES (age, metastasis, extent and size) classification system. J Med Assoc Thai 89: 484-489, 2006.
16. Michels JJ, Jacques M, Henry-Amar M and Bardet S: Prevalence and prognostic significance of tall cell variant of papillary thyroid carcinoma. Hum Pathol 38: 212-219, 2007. (Pubitemid 46096555)
17. Mazzaferri EL: Managing small thyroid cancers. JAMA 295: 2179-2182, 2006.
18. Mazzaferri EL and Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97: 418-428, 1994. (Pubitemid 24345593)
19. Fagin JA: Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid. Mol Endocrinol 16: 903-911, 2002.
20. Bongarzone I and Pierotti MA: The molecular basis of thyroid epithelial tumorigenesis. Tumori 89: 514-516, 2003. (Pubitemid 37541607)
21. Nikiforov YE: RET/PTC rearrangement in thyroid tumors. Endocrine Pathology 13: 3-16, 2002.
22. Tallini G: Molecular pathobiology of thyroid neoplasms. Endocr Pathol 13: 271-288, 2002.
23. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM and Fletcher JA: PAX8- PPARgamma1 fusion oncogene in human thyroid carcinoma. Science 289: 1357-1360, 2000. (Pubitemid 30656054)
24. McIver B, Grebe SK and Eberhardt NL: The PAX8/ PPARgamma fusion oncogene as a potential therapeutic target in follicular thyroid carcinoma. Curr Drug Targets Immune Endocr Metabol Disord 4: 221-234, 2004. (Pubitemid 39199358)
25. Nikiforova MN and Nikiforov YE: Molecular genetics of thyroid cancer: implications for diagnosis, treatment and prognosis. Expert Rev Mol Diagn 8: 83-95, 2008.
26. Garnett MJ and Marais R: Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6: 313-319, 2004. (Pubitemid 39361432)
27. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW and Sidransky D: BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95: 625-627, 2003. (Pubitemid 36553510)
28. Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K and Takenoshita S: BRAF mutations in papillary carcinomas of the thyroid. Oncogene 22: 6455-6457, 2003. (Pubitemid 37281692)
29. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE and Fagin JA: High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63: 1454-1457, 2003. (Pubitemid 36373628)
30. Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T and Yamashita S: Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88: 4393-4397, 2003. (Pubitemid 37153748)
31. Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V, Botelho T, Seruca R and Sobrinho-Simões M: BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22: 4578-4580, 2003.
32. Xu X, Quiros RM, Gattuso P, Ain KB and Prinz RA: High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res 63: 4561-4567, 2003. (Pubitemid 36951030)
33. Xing M: BRAF mutation in thyroid cancer. Endocr Relat Cancer 12: 245-262, 2005.
34. Pritchard C and McMahon M: Raf revealed in life-or-death decisions. Nat Genet 16: 214-215, 1997. (Pubitemid 27280198)
35. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773: 1263-1284, 2007. (Pubitemid 47125967)
36. Steelman LS, Abrams SL, Shelton JG, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM and McCubrey JA: Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle 9: 1629-1638, 2010.
37. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, et al: Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY) 3: 192-222, 2011.
38. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Bäsecke J, Stivala F, Donia M, Fagone P, et al: Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2: 135-164, 2011.
39. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J and Kohno M: Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18: 813-822, 1999. (Pubitemid 29080340)
40. Ciampi R and Nikiforov YE: RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology 148: 936-941, 2007.
41. Santoro M, Melillo RM and Fusco A: RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur J Endocrinol 155: 645-653, 2006. (Pubitemid 44857487)
42. Russo AE, Torrisi E, Bevelacqua Y, Perrotta R, Libra M, McCubrey JA, Spandidos DA, Stivala F and Malaponte G: Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol 34: 1481-1489, 2009.
43. Steelman LS, Navolanic PM, Franklin RA, Bonati A, Libra M, Stivala F, Martelli AM and McCubrey JA: Combining chemo-, hormonal and targeted therapies to treat breast cancer (Review). Mol Med Report 1: 139-160, 2008.
44. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417: 949-954, 2002. (Pubitemid 34716871)
45. Dhillon AS and Kolch W: Oncogenic B-Raf mutations: crystal clear at last. Cancer Cell 5: 303-304, 2004. (Pubitemid 38482064)
46. Hubbard SR: Oncogenic mutations in B-Raf: some losses yield gains. Cell 116: 764-766, 2004.
47. McCubrey JA, Steelman LS, Kempf CR, Chappell WH, Abrams SL, Stivala F, Malaponte G, Nicoletti F, Libra M, Bäsecke J, et al: Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol 226: 2762-2781, 2011.
48. Lima J, Trovisco V, Soares P, Máximo V, Magalhães J, Salvatore G, Santoro M, Bogdanova T, Tronko M, Abrosimov A, et al: BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 89: 4267-4271, 2004. (Pubitemid 39244424)
49. Trovisco V, Vieira de Castro I, Soares P, Maximo V, Silva P, Magalhaes J, Abrosimov A, Guiu XM and Sobrinho-Simões M: BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 202: 247-251, 2004.
50. Frattini M, Ferrario C, Bressan P, Balestra D, De Cecco L, Mondellini P, Bongarzone I, Collini P, Gariboldi M, Pilotti S, Pierotti MA and Greco A: Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene 23: 7436-7740, 2004.
51. Perren A, Schmid S, Locher T, Saremaslani P, Bonvin C, Heitz PU and Komminoth P: BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors. Endocr Relat Cancer 11: 855-860, 2004. (Pubitemid 40065557)
52. Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, Marino C, Avenia N, Rossi ED, Fadda G, et al: BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab 89: 2414-2420, 2004. (Pubitemid 38619884)
53. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, Rabes HM, Fagin JA and Nikiforov YE: Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115: 94-101, 2005. (Pubitemid 40385509)
54. Fusco A, Viglietto G and Santoro M: A new mechanism of BRAF activation in human thyroid papillary carcinomas. J Clin Invest 115: 20-23, 2005. (Pubitemid 40385497)
55. Knauf JA, Ma X, Smith EP, Zhang L, Mitsutake N, Liao XH, Refetoff S, Nikiforov YE and Fagin JA: Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 65: 4238-4245, 2005. (Pubitemid 40775662)
56. Mesa Jr C, Mirza M, Mitsutake N, Sartor M, Medvedovic M, Tomlinson C, Knauf JA, Weber GF and Fagin JA: 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 Res 66: 6521-6529, 2006. (Pubitemid 44085606)
57. Ouyang B, Knauf JA, Smith EP, Zhang L, Ramsey T, Yusuff N, Batt D and Fagin JA: Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res 12: 1785-1793, 2006.
58. Liu D, Liu Z, Condouris S and Xing M: BRAF V600E maintains proliferation, transformation, and tumorigenicity of BRAFmutant papillary thyroid cancer cells. J Clin Endocrinol Metab 92: 2264- 2271, 2007.
59. Salvatore G, Falco V, Salerno P, Nappi T, Pepe S, Troncone G, Carlomagno F, Melillo R, Wilhelm SM and Santoro M: BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res 12: 1623-1629, 2006.
60. Mitsutake N, Knauf JA, Mitsutake S, Mesa Jr C, Zhang L and Fagin JA: Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Res 65: 2465-2473, 2005. (Pubitemid 40490159)
61. Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, Caiazzo F, Basolo F, Giannini R, Kruhoffer M, et al: The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest 115: 1068-1081, 2005. (Pubitemid 40489412)
62. Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K, 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.
63. Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, Sidransky D and Umbricht CB: Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab 90: 4011-4018, 2005. (Pubitemid 41058165)
64. Hu S, Liu DX, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney 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. (Pubitemid 44546951)
65. Hou P, Liu D and Xing M: Genome-wide alterations in gene methylation by the BRAF V600E mutation in papillary thyroid cancer cells. Endocr Relat Cancer 18: 687-697, 2011.
66. Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, Decaussin M, Peix JL, Bournaud C, Orgiazzi J, et al: Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab 90: 3028-3035, 2005. (Pubitemid 40686360)
67. Anand-Apte B, Bao L, Smith R, Iwata K, Olsen BR, Zetter B and Apte SS: A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol 74: 853-862, 1996. (Pubitemid 126733745)
68. Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A and Anand-Apte B: A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9: 407-415, 2003. (Pubitemid 36460074)
69. Chou CK, Chen RF, Chou FF, Chang HW, Chen YJ, Lee YF, Yang KD, Cheng JT, Huang CC and Liu RT: 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.
70. Cahill S, Smyth P, Denning K, Flavin R, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ and Sheils O: Effect of BRAFV600E mutation on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer 6: 21, 2007.
71. Yoon H, He H, Nagy R, Davuluri R, Suster S, Schoenberg D, Pellegata N and Chapelle AL: Identification of a novel noncoding RNA gene, NAMA, that is downregulated in papillary thyroid carcinoma with BRAF mutation and associated with growth arrest. Int J Cancer 121: 767-775, 2007. (Pubitemid 47106205)
72. Palona I, Namba H, Mitsutake N, Starenki D, Podtcheko A, Sedliarou I, Ohtsuru A, Saenko V, Nagayama Y, Umezawa K and Yamashita S: BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kB activation. Endocrinology 147: 5699-5707, 2006. (Pubitemid 44833486)
73. Karin M: Nuclear factor-kB in cancer development and progression. Nature 441: 431-436, 2006.
74. Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25: 9-34, 2006. (Pubitemid 43723979)
75. Jo YS, Li S, Song JH, Kwon KH, Lee JC, Rha SY, Lee HJ, Sul JY, Kweon GR, Ro HK, Kim JM and Shong M: Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer. J Clin Endocrinol Metab 91: 3667-3670, 2006. (Pubitemid 44402153)
76. Grabellus F, Worm K, Schmid KW and Sheu-Grabellus SY: The BRAF V600E mutation in papillary thyroid carcinomas is associated with glucose transporter 1 (GLUT1) overexpression. Thyroid 22: 377-382, 2012.
77. Nilsson M: Iodide handling by the thyroid epithelial cell. Exp Clin Endocrinol Diabetes 109: 13-17, 2001.
78. Arturi F, Russo D, Bidart JM, Scarpelli D, Schlumberger M and Filetti S: Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors. Eur J Endocrinol 145: 129-135, 2001. (Pubitemid 32707598)
79. Ringel MD, Anderson J, Souza SL, Burch HB, Tambascia M, Shriver CD and Tuttle RM: Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer. Mod Pathol 14: 289-296, 2001. (Pubitemid 32298914)
80. Durante C, Puxeddu E, Ferretti E, Morisi R, Moretti S, Bruno R, Barbi F, Avenia N, Scipioni A, Verrienti A, et al: BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab 92: 2840-2843, 2007. (Pubitemid 47037399)
81. Mian C, Barollo S, Pennelli G, Pavan N, Rugge M, Pelizzo MR, Mazzarotto R, Casara D, Nacamulli D, Mantero F, et al: Molecular characteristics in papillary thyroid cancers (PTCs) with no (131)I uptake. Clin Endocrinol 68: 108-116, 2008. (Pubitemid 350243490)
82. Di Cristofaro J, Silvy M, Lanteaume A, Marcy M, Carayon P and De Micco C: Expression of tpo mRNA in thyroid tumors: quantitative PCR analysis and correlation with alterations of ret, Braf, ras and pax8 genes. Endocr Relat Cancer 13: 485-495, 2006. (Pubitemid 43886671)
83. +/Itargeting to the membrane. Endocr Relat Cancer 13: 257-269, 2006.
84. Liu D, Hu S, Hou P, Jiang D, Condouris S and 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 13: 1341-1349, 2007. (Pubitemid 46424076)
85. Ikuyama S, Niller HH, Shimura H, Akamizu T and Kohn LD: Characterization of the 5-flanking region of the rat thyrotropin receptor gene. Mol Endocrinol 6: 793-804, 1992.
86. Yokomori N, Tawata M, Saito T, Shimura H and Onaya T: Regulation of the rat thyrotropin receptor gene by the methylationsensitive transcription factor GA-binding protein. Mol Endocrinol 12: 1241-1249, 1998. (Pubitemid 30659050)
87. Xing M, Usadel H, Cohen Y, Tokumaru Y, Guo Z, Westra WB, Tong BC, Tallini G, Udelsman R, Califano JA, Ladenson PW and Sidransky D: Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res 63: 2316-2321, 2003. (Pubitemid 36538643)
88. Schagdarsurengin U, Gimm O, Dralle H, Hoang-Vu C and Dammann R: CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma. Thyroid 16: 633-642, 2006.
89. Xing M: BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev 28: 742-762, 2007.
90. Abrosimov A, Saenko V, Rogounovitch T, Namba H, Lushnikov E, Mitsutake N and Yamashita S: Different structural components of conventional papillary thyroid carcinoma display mostly identical BRAF status. Int J Cancer 120: 196-200, 2007. (Pubitemid 44901936)
91. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW and Nikiforov YE: Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 30: 216-222, 2006. (Pubitemid 43740191)
92. Fugazzola L, Mannavola D, Cirello V, Vannucchi G, Muzza M, Vicentini L and Beck-Peccoz P: BRAF mutations in an Italian cohort of thyroid cancers. Clin Endocrinol 61: 239-243, 2004. (Pubitemid 39093120)
93. Fugazzola L, Puxeddu E, Avenia N, Romei C, Cirello V, Cavaliere A, Faviana P, Mannavola D, Moretti S, Rossi S, et al: Correlation between B-RAFV600E mutation and clinicopathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr Relat Cancer 13: 455-464, 2006. (Pubitemid 43886668)
94. Jin L, Sebo TJ, Nakamura N, Qian X, Oliveira A, Majerus JA, Johnson MR and Lloyd RV: BRAF mutation analysis in fine needle aspiration (FNA) cytology of the thyroid. Diagn Mol Pathol 15: 136-143, 2006. (Pubitemid 44325474)
95. Kebebew E, Weng J, Bauer J, Ranvier G, Clark OH, Duh QY, Shibru D, Bastian B and Griffin A: The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 246: 466-471, 2007.
96. Kim KH, Kang DW, Kim SH, Seong IO and Kang DY: Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J 45: 818-821, 2004. (Pubitemid 39545368)
97. Kim KH, Suh KS, Kang DW and Kang DY: Mutations of the BRAF gene in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Pathol Int 55: 540-545, 2005.
98. Kim TY, Kim WB, Song JY, Rhee YS, Gong G, Cho YM, Kim SY, Kim SC, Hong SJ and Shong YK: The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol (Oxf) 63: 588-593, 2005. (Pubitemid 41626756)
99. Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC, Hong SJ and Shong YK: 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.
100. Kim J, Giuliano AE, Turner RR, Gaffney RE, Umetani N, Kitago M, Elashoff D and Hoon DS: Lymphatic mapping establishes the role of BRAF gene mutation in papillary thyroid carcinoma. Ann Surg 244: 799-804, 2006. (Pubitemid 44629955)
101. Liu RT, Chen YJ, Chou FF, Li CL, Wu WL, Tsai PC, Huang CC and Cheng JT: No correlation between BRAFV600E mutation and clinicopathological features of papillary thyroid carcinomas in Taiwan. Clin Endocrinol (Oxf) 63: 461-466, 2005.
102. Lupi C, Giannini R, Ugolini C, Proietti A, Berti P, Minuto M, Materazzi G, Elisei R, Santoro M, Miccoli P and Basolo F: Association of BRAF V600E mutation with poor clinicopathologic outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 92: 4085-4090, 2007. (Pubitemid 350074715)
103. Lee JH, Lee ES, Kim YS, Won NH and Chae YS: BRAF mutation and AKAP9 expression in sporadic papillary thyroid carcinomas. Pathology 38: 201-204, 2006. (Pubitemid 43879713)
104. Mitsiades CS, Negri J, McMullan C, McMillin DW, Sozopoulos E, Fanourakis G, Voutsinas G, Tseleni-Balafouta S, Poulaki V, Batt D and Mitsiades N: Targeting BRAFV600E in thyroid carcinoma: therapeutic implications. Mol Cancer Ther 6: 1070-1078, 2007. (Pubitemid 46554578)
105. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, 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. (Pubitemid 37452745)
106. Park SY, Park YJ, Lee YJ, Lee HS, Choi SH, Choe G, Jang HC, Park SH, Park do J and Cho BY: Analysis of differential BRAF (V600E) mutational status in multifocal papillary thyroid carcinoma: evidence of independent clonal origin in distinct tumor foci. Cancer 107: 1831-1838, 2006. (Pubitemid 44582952)
107. Rodolico V, Cabibi D, Pizzolanti G, Richiusa P, Gebbia N, Martorana A, Russo A, Amato MC, Galluzzo A and Giordano C: 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. (Pubitemid 47435591)
108. Sedliarou I, Saenko V, Lantsov D, Rogounovitch T, Namba H, Abrosimov A, Lushnikov E, Kumagai A, Nakashima M, Meirmanov S, et al: The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. Int J Oncol 25: 1729-1735, 2004.
109. Trovisco V, Soares P, Preto A, de Castro IV, Lima J, Castro P, Maximo V, Botelho T, Moreira S, Meireles AM, et al: Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness. Virchows Arch 446: 589-595, 2005. (Pubitemid 40922263)
110. Xing M, Westra WH, Tufano RP, et al: BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90: 6373-6379, 2005. (Pubitemid 41759286)
111. Powell N, Jeremiah S, Morishita M, Dudley E, Bethel J, Bogdanova T, Tronko M and Thomas G: Frequency of BRAF T1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. J Pathol 205: 558-564, 2005. (Pubitemid 40514828)
112. Sapio MR, Posca D, Troncone G, Pettinato G, Palombini L, Rossi G, Fenzi G and Vitale M: Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA). Eur J Endocrinol 154: 341-348, 2006.
113. Frasca F, Nucera C, Pellegriti G, Gangemi P, Attard M, Stella M, Loda M, Vella V, Giordano C, Trimarchi F, et al: BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer 15: 191-205, 2008. (Pubitemid 351449739)
114. Cañadas Garre M, López de la Torre Casares M, Becerra Massare P, López Nevot MÁ, Villar Del Moral J, Muñoz Pérez N, Vílchez Joya R, Montes Ramírez R and Llamas Elvira JM: BRAF(T1799A) mutation in the primary tumor as a marker of risk, recurrence, or persistence of papillary thyroid carcinoma. Endocrinol Nutr 58: 175-184, 2011.
115. Chakraborty A, Narkar A, Mukhopadhyaya R, Kane S, D'Cruz A and Rajan MG: BRAF (V600E) Mutation in papillary phyroid carcinoma: significant association with node metastases and extra thyroidal invasion. Endocr Pathol 23:83-93, 2012.
116. Nam JK, Jung CK, Song BJ, Lim DJ, Chae BJ, Lee NS, Park WC, Kim JS, Jung SS and Bae JS: Is the BRAF(V600E) mutation useful as a predictor of preoperative risk in papillary thyroid cancer? Am J Surg 203: 436-441, 2011.
117. Kim SJ, Lee KE, Myong JP, Park JH, Jeon YK, Min HS, Park SY, Jung KC, Koo do H and Youn YK: BRAF(V600E) mutation is associated with tumor aggressiveness in papillary thyroid cancer. Word J Surg 36: 310-317, 2012.
118. Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D and Westra WH: BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol 17: 1359-1363, 2004. (Pubitemid 39472990)
119. Quiros RM, Ding HG, Gattuso P, Prinz RA and Xu X: Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 103: 2261-2268, 2005. (Pubitemid 40686569)
120. Takano T, Ito Y, Hirokawa M, Yoshida H and Miyauchi A: BRAF V600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas. Br J Cancer 96: 1549-1553, 2007. (Pubitemid 46762958)
121. Ito Y, Yoshida H, Maruo R, et al: BRAF mutation in papillary thyroid carcinoma in a Japanese population: its lack of correlation with high-risk clinicopathologic features and disease-free survival of patients. Endocrine J 56: 89-97, 2009.
122. Howell GM, Carty SE, Armstrong MJ, Lebeau SO, Hodak SP, Coyne C, Stang MT, McCoy KL, Nikiforova MN, Nikiforov YE and Yip L: Both BRAF V600E mutation and older age (≥65 years) are associated with recurrent papillary thyroid cancer. Ann Surg Oncol 18: 3566-3571, 2011.
123. Ain KB: Management of undifferentiated thyroid cancer. Baillieres Best Pract Res Clin Endocrinol Metab 14: 615-629, 2000.
124. Chung KW, Yang SK, Lee GK, Kim EY, Kwon S, Lee SH, Park do J, Lee HS, Cho BY, Lee ES and Kim SW: Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis, especially in BRAF600E mutation-prevalent area. Clin Endocrinol (Oxf) 65: 660-666, 2006. (Pubitemid 44583829)
125. Patel A, Klubo-Gwiezdzinska J, Hoperia V, Larin A, Jensen K, Bauer A and Vasko V: BRAF(V600E) mutation analysis from May-Grünwald Giemsa-stained cytological samples as an adjunct in identification of high-risk papillary thyroid carcinoma. Endocr Pathol 22: 195-199, 2011.
126. Rowe LR, Bentz BG and Bentz JS: Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules. Cytojournal 3: 10, 2006.
127. Marchetti I, Lessi F, Mazzanti CM, Bertacca G, Elisei R, Coscio GD, Pinchera A and Bevilacqua G: A morpho-molecular diagnosis of papillary thyroid carcinoma: BRAF V600E detection as an important tool in preoperative evaluation of fineneedle aspirates. Thyroid 19: 837-842, 2009.
128. Colanta A, Lin O, Tafe L, Ghossein R, Nafa K, Mitchell T, Ladanyi M and Arcila M: BRAF mutation analysis of fine-needle aspiration biopsies of papillary thyroid carcinoma: Impact on diagnosis and prognosis. Acta Cytol 55: 563-569, 2011.
129. Bollag G, Hirth P, Tsai J, et al: Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467: 596-569, 2010.
130. Nucera C, Porrello A, Antonello ZA, Mekel M, Nehs MA, Giordano TJ, Gerald D, Benjamin LE, Priolo C, Puxeddu E, et al: B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression Proc Natl Acad Sci USA 107: 10649-10654, 2010.
131. Nucera C, Nehs MA, Mekel M, Zhang X, Hodin R, Lawler J, Nose V and Parangi S: A novel orthotopic mouse model of human anaplastic thyroid carcinoma. Thyroid 19: 1077-1084, 2009.
132. Liu D, Liu Z, Jiang D, Dackiw AP and Xing M: Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations. J Clin Endocrinol Metab 92: 4686-4695, 2007. (Pubitemid 350223445)
133. Henderson YC, Fredrick MJ and Clayman GL: Differential responses of human papillary thyroid cancer cell lines carrying the RET/PTC1 rearrangement or a BRAF mutation to MEK1/2 inhibitors. Arch Otolaryngol Head Neck Surg 133: 810-815, 2007. (Pubitemid 47295764)
134. Wallace EM, Lyssikatos JP, Yeh T, Winkler JD and Koch K: Progress towards
135. Wang D, Boerner SA, Winkler JD, and LoRusso PM: Clinical experience of MEK inhibitors in cancer therapy. Biochim Biophys Acta 1773: 1248-1255, 2007. (Pubitemid 47161034)