Skip to main content

Advertisement

Log in

BRAFV600E mutation in Turkish patients with papillary thyroid cancer: strong correlation with indicators of tumor aggressiveness

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Papillary thyroid cancer (PTC) constitutes more than 90 % of the thyroid cancers. MAP kinase/ERK pathway plays an important role in the development of several cancers. BRAF which is a member of Raf-kinase family activates this way. BRAF gene activating mutations lead to neoplastic transformation in thyroid follicle cells. In PTC, this mutation itself is a poor prognostic sign independent of other clinicopathological characteristics. We evaluated BRAFV600E mutation and clinical–pathological characteristics in Turkish population with PTC. We assessed 109 patients with PTC (88 female, 21 male). The average age was 38.7 ± 9.9 (17–71). BRAFV600E mutation was detected using polymerase chain reaction and fluorescent melting curve analysis. The results show that BRAFV600E mutation rate was found in 39.45 % of our patients. We observed that BRAFV600E mutation was significantly higher in men, in tumors larger than 1 cm in size, and in patients with classical PTC. Moreover, statistically significant correlations of BRAFV600E with indicators of tumor aggressiveness such as thyroid capsular invasion, multifocality, lymph node metastasis, and extrathyroidal spread were found. Patient groups below and over the age of 45 did not differ in mutation frequency. Patients with micro-PTC were evaluated separately, it was found that BRAFV600E mutation was more frequent in the classic type and that lymph node metastasis rate significantly increased when the mutation was present. We concluded that BRAFV600E was correlated with indicators of tumor aggressiveness in our study population. This fact is taken into consideration in treatment and follow-up of our patients with PTC and positive BRAFV600E mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. A. Jemal, R. Siegel, J. Xu, E. Ward, Cancer statistcs. CA Cancer J. Clin. 60, 277–300 (2010)

    Article  PubMed  Google Scholar 

  2. Y.X. Wang, L. Zhao, X.Y. Wang, C.M. Liu, S.G. Yu, Association between E-cadherin (CDH1) polymorphisms and papillary thyroid carcinoma risk in Han Chinese population. Endocrine (2011). doi:10.1007/s12020-011-9582-y

  3. L. Pagano, M. Caputo, M.T. Samà, V. Garbaccio, M. Zavattaro, M.G. Mauri, F. Prodam, P. Marzullo, R. Boldorini, G. Valente, G. Aimaretti, Clinical–pathological changes in differentiated thyroid cancer (DTC) over time (1997–2010): data from the University Hospital “Maggiore della Carità” in Novara. Endocrine (2012). doi:10.1007/s12020-012-9612-4

  4. E.L. Mazzaferri, S.M. Jhiang, Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am. J. Med. 97, 418–428 (1994)

    Article  PubMed  CAS  Google Scholar 

  5. D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, S.L. Lee, S.J. Mandel, E.L. Mazzaferri, B. McIver, S.I. Sherman, American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16, 109–142 (2006)

    Article  PubMed  Google Scholar 

  6. P. Kaldrymides, I. Kostoglou-Athanassiou, A. Gkountouvas, E. Veniou, N. Ziras, Partial remission of metastatic papillary thyroid carcinoma with sunitinib. Report of a case and review of the literature. Endocrine 37, 6–10 (2010)

    Article  PubMed  CAS  Google Scholar 

  7. M. Rivera, R.A. Ghossein, H. Schoder, D. Gomez, S.M. Larson, R.M. Tuttle, Histopathologic characterization of radioactive iodine-refractory fluorodeoxyglucose-positron emission tomography-positive thyroid carcinoma. Cancer 113, 48–56 (2008)

    Article  PubMed  Google Scholar 

  8. J.D. Lin, T.C. Chao, C. Hsueh, Clinical characteristics of poorly differentiated thyroid carcinomas compared with classical papillary thyroid carcinomas. Clin. Endocrinol. (Oxf.) 66, 224–228 (2007)

    Article  Google Scholar 

  9. M.J. Robinson, M.H. Cobb, Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9, 180–186 (1997)

    Article  PubMed  CAS  Google Scholar 

  10. E.T. Kimura, M.N. Nikiforova, Z. Zhu, J.A. Knauf, Y.E. Nikiforov, J.A. Fagin, 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)

    PubMed  CAS  Google Scholar 

  11. R.M. Melillo, M.D. Castellone, V. Guarino, V. De Falco, A.M. Cirafici, G. Salvatore, F. Caiazzo, F. Basolo, R. Giannini, M. Kruhoffer, T. Orntoft, A. Fusco, M. Santoro, 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)

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. K.E. Mercer, C.A. Pritchard, Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim. Biophys. Acta 1653, 25–40 (2003)

    PubMed  CAS  Google Scholar 

  14. M.J. Garnett, R. Marais, Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313–319 (2004)

    Article  PubMed  CAS  Google Scholar 

  15. R. Ciampi, Y.E. Nikiforov, RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology 148, 936–941 (2007)

    Article  PubMed  CAS  Google Scholar 

  16. M.N. Nikiforova, E.T. Kimura, M. Gandhi, P.W. Biddinger, J.A. Knauf, F. Basolo, Z. Zhu, R. Giannini, G. Salvatore, A. Fusco, M. Santoro, J.A. Fagin, Nikiforov YE.BRAF mutations in tumors are restricted to papillary carcinomas and anaplastic or poorly differantiated carcinomas arising from papillary carcinomas. J. Clin. Endocrinol. Metab. 88, 5399–5404 (2003)

    Article  PubMed  CAS  Google Scholar 

  17. M. Xing, BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 12, 245–262 (2005)

    Article  PubMed  CAS  Google Scholar 

  18. M. Xing, BRAF mutation in papillary thyroid cancer: Pathogenic role, molecular bases, and clinical implications. Endocr. Rev. 28, 742–762 (2007)

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. C. Durante, E. Puxeddu, E. Ferretti, R. Morisi, S. Moretti, R. Bruno, F. Barbi, N. Avenia, A. Scipioni, A. Verrienti, E. Tosi, A. Cavaliere, A. Gulino, S. Filetti, D. Russo, BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J. Clin. Endocrinol. Metab. 92, 2840–2843 (2007)

    Article  PubMed  CAS  Google Scholar 

  21. C. Mian, S. Barollo, G. Pennelli, N. Pavan, M. Rugge, M.R. Pelizzo, R. Mazzarotto, D. Casara, D. Nacamulli, F. Mantero, G. Opocher, B. Busnardo, M.E. Girelli, Molecular characteristics in papillary thyroid cancers (PTCs) with no 131I uptake. Clin. Endocrinol. (Oxf.) 68, 108–116 (2008)

    Article  CAS  Google Scholar 

  22. M. Xing, W.H. Westra, R.P. Tufano, Y. Cohen, E. Rosenbaum, K.J. Rhoden, K.A. Carson, V. Vasko, A. Larin, G. Tallini, S. Tolaney, E.H. Holt, P. Hui, C.B. Umbricht, S. Basaria, M. Ewertz, A.P. Tufaro, J.A. Califano, M.D. Ringel, M.A. Zeiger, D. Sidransky, P.W. Ladenson, BRAF mutation predicts a poorer clinical prognosis for papillar thyroid cancer. J. Clin. Endocrinol. Metab. 90, 6373–6379 (2005)

    Article  PubMed  CAS  Google Scholar 

  23. R. Elisei, C. Ugolini, D. Viola, C. Lupi, A. Biagini, R. Giannini, C. Romei, P. Miccoli, A. Pinchera, Basolo F 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)

    Article  PubMed  CAS  Google Scholar 

  24. UICC, in TNM Classification of Malignant Tumors, 6th edn., ed. by L.H. Sobin, C.H. Wittekind (Wiles-Liss, New York, 2002)

    Google Scholar 

  25. L.R. Rowe, B.G. Bentz, J.S. Bentz, Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules. CytoJournal 3, 10 (2006)

    Article  PubMed  Google Scholar 

  26. B. Stanojevic, R. Dzodic, V. Saenko, Z. Milovanovic, G. Pupic, O. Zivkovic, I. Markovic, I. Djurisic, M. Buta, B. Dimitrijevic, T. Rogounovitch, N. Mitsutake, M. Mine, Y. Shibata, M. Nakashima, S. Yamashita, Mutational and clinico-pathological analysis of papillary thyroid carcinoma in Serbia. Endocr. J. 58, 381–393 (2011)

    Article  PubMed  CAS  Google Scholar 

  27. V. Trovisco, P. Soares, M. Sobrinho-Simoes, B-RAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas. Hum. Pathol. 37, 781–786 (2006)

    Article  PubMed  CAS  Google Scholar 

  28. X. Xu, R.M. Quiros, P. Gattuso, K.B. Ain, R.A. Prinz, High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 1, 4561–4567 (2003)

    Google Scholar 

  29. C. Lupi, R. Giannini, C. Ugolini, A. Proietti, P. Berti, M. Minuto, G. Materazzi, R. Elisei, M. Santoro, P. Miccoli, Basolo F 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)

    Article  PubMed  CAS  Google Scholar 

  30. Y. Ito, H. Yoshida, R. Maruo, S. Morita, T. Takano, M. Hirokawa, T. Yabuta, M. Fukushima, H. Inoue, C. Tomoda, M. Kihara, T. Uruno, T. Higashiyama, Y. Takamura, A. Miya, K. Kobayashi, F. Matsuzuka, A. Miyauchi, BRAF mutation in papillary thyroid carcinoma in a Japanese population: its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocr. J. 56, 89–97 (2009)

    Article  PubMed  CAS  Google Scholar 

  31. A. Mathur, W. Moses, R. Rahbari, E. Khanafshar, Q.Y. Duh, O. Clark, E. Kebebew, Higher rate of BRAF mutation in papillary thyroid cancer over time: A single-institution study. Cancer 117, 4390–4395 (2011)

    Article  PubMed  CAS  Google Scholar 

  32. D. Ahn, J.S. Park, J.H. Sohn, J.H. Kim, S.K. Park, A.N. Seo, J.Y. Park, BRAF(V600E) mutation does not serve as a prognostic factor in Korean patients with papillary thyroid carcinoma. Auris Nasus Larynx 39, 198–203 (2012)

    Article  PubMed  Google Scholar 

  33. T.H. Kim, Y.J. Park, J.A. Lim, H.Y. Ahn, E.K. Lee, Y.J. Lee, K.W. Kim, S.K. Hahn, Y.K. Youn, K.H. Kim, B.Y. Cho, D.J. Park, The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer (2011). doi:10.1002/cncr.26500

    Google Scholar 

  34. F. Frasca, C. Nucera, G. Pellegriti, P. Gangemi, M. Attard, M. Stella, M. Loda, V. Vella, C. Giordano, F. Trimarchi, E. Mazzon, A. Belfiore, R. Vigneri, BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocr. Relat. Cancer 15, 191–205 (2008)

    Article  PubMed  CAS  Google Scholar 

  35. E. Kebebew, J. Weng, J. Bauer, G. Ranvier, O.H. Clark, Q.Y. Duh, D. Shibru, B. Bastian, A. Griffin, The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann. Surg. 246, 466–471 (2007)

    Article  PubMed  Google Scholar 

  36. A. Czarniecka, D. Rusinek, E. Stobiecka, J. Krajewska, M. Kowal, A. Kropińska, J. Zebracka, M. Kowalska, J. Włoch, A. Maciejewski, D. Handkiewicz-Junak, Occurrence of BRAF mutations in a Polish cohort of PTC patients—preliminary results. Endokrynol. Pol. 61, 462–466 (2010)

    PubMed  Google Scholar 

  37. V. Trovisco, P. Soares, A. Preto, I.V. de Castro, J. Lima, P. Castro, V. Máximo, T. Botelho, S. Moreira, A.M. Meireles, J. Magalhães, A. Abrosimov, J. Cameselle-Teijeiro, M. Sobrinho-Simões, 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)

    Article  PubMed  CAS  Google Scholar 

  38. L. Fugazzola, E. Puxeddu, N. Avenia, C. Romei, V. Cirello, A. Cavaliere, P. Faviana, D. Mannavola, S. Moretti, S. Rossi, M. Sculli, V. Bottici, P. Beck-Peccoz, F. Pacini, A. Pinchera, F. Santeusanio, R. Elisei, Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr. Relat. Cancer 13, 455–464 (2006)

    Article  PubMed  CAS  Google Scholar 

  39. G.M. Howell, S.E. Carty, M.J. Armstrong, S.O. Lebeau, S.P. Hodak, C. Coyne, M.T. Stang, K.L. McCoy, M.N. Nikiforova, Y.E. Nikiforov, L. Yip, Both BRAF V600E mutation and older age (≥65 years) are associated with recurrent papillary thyroid cancer. Ann. Surg. Oncol. 19, 877–883 (2011)

    Google Scholar 

  40. L.A. Niemeier, H. Kuffner Akatsu, C. Song, S.E. Carty, S.P. Hodak, L. Yip, R.L. Ferris, G.C. Tseng, R.R. Seethala, S.O. Lebeau, M.T. Stang, C. Coyne, J.T. Johnson, A.F. Stewart, Y.E. Nikiforov, A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma. Cancer (2011). doi:10.1002/cncr.26425

    PubMed  Google Scholar 

  41. Y.J. Park, Y.A. Kim, Y.J. Lee, S.H. Kim, S.Y. Park, K.W. Kim, J.K. Chung, Y.K. Youn, K.H. Kim, J. Park do, B.Y. Cho, Papillary microcarcinoma in comparison with larger papillary thyroid carcinoma in BRAF(V600E)mutation, clinicopathological features, and immunohistochemical findings. Head Neck 32, 38–45 (2010)

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Neslihan Kurtulmus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurtulmus, N., Duren, M., Ince, U. et al. BRAFV600E mutation in Turkish patients with papillary thyroid cancer: strong correlation with indicators of tumor aggressiveness. Endocrine 42, 404–410 (2012). https://doi.org/10.1007/s12020-012-9651-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-012-9651-x

Keywords

Navigation