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A Novel Complex BRAF Mutation Detected in a Solid Variant of Papillary Thyroid Carcinoma

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Abstract

BRAF gene mutations are identified in about 45% of papillary thyroid carcinomas (PTC) and represent the most common genetic event in this tumor. Here, we report a case of PTC, solid variant, with a complex BRAF mutation that involves one nucleotide substitution, C1796T, and a CTT triplet insertion, 1798_1799insCTT, located on the same allele. This mutation leads to the replacement of a threonine with an isoleucine, T599I, and replacement of a valine with an alanine and a leucine, V600delinsAL. This mutation was identified both in the preoperative fine needle aspirate sample and in the surgical specimen after total thyroidectomy. Other rare BRAF mutations in PTC are reviewed.

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References

  1. Fagin JA. Genetics of papillary thyroid cancer initiation: implications for therapy. Trans Am Clin Climatol Assoc 116:259–69; discussion 269–271, 2005.

    PubMed  Google Scholar 

  2. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, 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(7):1454–7, 2003.

    PubMed  CAS  Google Scholar 

  3. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer, 6(4):292–306, 2006. doi:10.1038/nrc1836.

    Article  PubMed  CAS  Google Scholar 

  4. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol, 30(2):216–22, 2006. doi:10.1097/01.pas.0000176432.73455.1b.

    Article  PubMed  Google Scholar 

  5. Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, 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(44):6646–56, 2005. doi:10.1038/sj.onc.1208822.

    Article  PubMed  CAS  Google Scholar 

  6. Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, 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(3):364–8, 2006. doi:10.1111/j.1365-2265.2006.02605.x.

    Article  CAS  Google Scholar 

  7. Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab, 88(9):4393–7, 2003. doi:10.1210/jc.2003-030305.

    Article  PubMed  CAS  Google Scholar 

  8. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, 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(11):5399–404, 2003. doi:10.1210/jc.2003-030838.

    Article  PubMed  CAS  Google Scholar 

  9. 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, 13(1):257–69, 2006. doi:10.1677/erc.1.01119.

    Article  PubMed  CAS  Google Scholar 

  10. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab, 90(12):6373–9, 2005. doi:10.1210/jc.2005-0987.

    Article  PubMed  CAS  Google Scholar 

  11. Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini 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(10):3943–9, 2008. doi:10.1210/jc.2008-0607.

    Article  PubMed  CAS  Google Scholar 

  12. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature, 417(6892):949–54, 2002. doi:10.1038/nature00766.

    Article  PubMed  CAS  Google Scholar 

  13. 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, 116(6):855–67, 2004. doi:10.1016/S0092-8674(04)00215-6.

    Article  PubMed  CAS  Google Scholar 

  14. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst, 95(8):625–7, 2003.

    Article  PubMed  CAS  Google Scholar 

  15. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer, 12(2):245–262, 2005. doi:10.1677/erc.1.0978.

    Article  PubMed  CAS  Google Scholar 

  16. Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA, 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(10):5175–80, 2004. doi:10.1210/jc.2003-032221.

    Article  PubMed  CAS  Google Scholar 

  17. Volante M, Collini P, Nikiforov YE, Sakamoto A, Kakudo K, Katoh R, et al. Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am J Surg Pathol, 31(8):1256–64, 2007. doi:10.1097/PAS.0b013e3180309e6a.

    Article  PubMed  Google Scholar 

  18. Trovisco V, Vieira de Castro I, Soares P, Maximo V, Silva P, Magalhaes J, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol, 202(2):247–51, 2004. doi:10.1002/path.1511.

    Article  PubMed  CAS  Google Scholar 

  19. Trovisco V, Soares P, Preto A, de Castro IV, Lima J, Castro P, 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(6):589–95, 2005. doi:10.1007/s00428-005-1236-0.

    Article  CAS  Google Scholar 

  20. Zhang BH, Guan KL. Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. Embo J, 19(20):5429–39, 2000. doi:10.1093/emboj/19.20.5429.

    Article  PubMed  CAS  Google Scholar 

  21. Trovisco V, Soares P, Soares R, Magalhaes J, Sa-Couto P, Sobrinho-Simoes M. A new BRAF gene mutation detected in a case of a solid variant of papillary thyroid carcinoma. Hum Pathol, 36(6):694–7, 2005. doi:10.1016/j.humpath.2005.04.011

    Article  PubMed  CAS  Google Scholar 

  22. Oler G, Ebina KN, Michaluart P, Jr, Kimura ET, Cerutti J. Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis reveals a new mutation in metastasis. Clin Endocrinol (Oxf), 62(4):509–11, 2005. doi:10.1111/j.1365-2265.2005.02235.x.

    Article  CAS  Google Scholar 

  23. Hou P, Liu D, Xing M. Functional characterization of the T1799–1801del and A1799–1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle, 6(3):377–9, 2007.

    PubMed  CAS  Google Scholar 

  24. Carta C, Moretti S, Passeri L, Barbi F, Avenia N, Cavaliere A, 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(1):105–9, 2006. doi:10.1111/j.1365-2265.2005.02401.x.

    Article  CAS  Google Scholar 

  25. Trovisco V, Couto JP, Cameselle-Teijeiro J, de Castro IV, Fonseca E, Soares P, et al. Acquisition of BRAF gene mutations is not a requirement for nodal metastasis of papillary thyroid carcinoma. Clin Endocrinol (Oxf) 69:683–685, 2008.

    Article  CAS  Google Scholar 

  26. Santarpia L, Sherman SI, Marabotti A, Clayman GL, El-Naggar AK. Detection and molecular characterization of a novel BRAF activated domain mutation in follicular variant of papillary thyroid carcinoma. Hum Pathol (in press), 2009, Feb 4.

  27. 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, 115(1):94–101, 2005.

    PubMed  CAS  Google Scholar 

  28. Nikiforov YE, Erickson LA, Nikiforova MN, Caudill CM, Lloyd RV. Solid variant of papillary thyroid carcinoma: incidence, clinical–pathologic characteristics, molecular analysis, and biologic behavior. Am J Surg Pathol, 25(12):1478–84, 2001. doi:10.1097/00000478-200112000-00002.

    Article  PubMed  CAS  Google Scholar 

  29. De Falco V, Giannini R, Tamburrino A, Ugolini C, Lupi C, Puxeddu E, et al. Functional characterization of the novel T599I-VKSRdel BRAF mutation in a follicular variant papillary thyroid carcinoma. J Clin Endocrinol Metab, 93(11):4398–4402, 2008.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Simion Chiosea, Marina Nikiforova, Hui Zuo, Manoj Gandhi, Raja R. Seethala, N. Paul Ohori & Yuri Nikiforov

  2. Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Jennifer Ogilvie

  3. Department of Pathology, Presbyterian Hospital, University of Pittsburgh Medical Center, PUH A616.2, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Simion Chiosea

Authors
  1. Simion Chiosea
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  2. Marina Nikiforova
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  3. Hui Zuo
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  4. Jennifer Ogilvie
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  5. Manoj Gandhi
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  6. Raja R. Seethala
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  7. N. Paul Ohori
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  8. Yuri Nikiforov
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Correspondence to Simion Chiosea.

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Chiosea, S., Nikiforova, M., Zuo, H. et al. A Novel Complex BRAF Mutation Detected in a Solid Variant of Papillary Thyroid Carcinoma. Endocr Pathol 20, 122–126 (2009). https://doi.org/10.1007/s12022-009-9073-3

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  • DOI: https://doi.org/10.1007/s12022-009-9073-3

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