Skip to main content
SpringerLink
Log in

Alterations of the BRAF gene in thyroid tumors

  • Review
  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

BRAF belongs to the RAF family of protein kinases that are important components of the MAPK signaling pathway mediating cell growth, differentiation and survival. Activating point mutation of the BRAF gene resulting in V600E (previously designated as V599E) is a common event in thyroid papillary carcinoma, being found in approx 40% of this tumor. It has strong association with classical papillary carcinoma and tall cell and possibly Warthin-like variants. This mutation also occurs in thyroid poorly differentiated and anaplastic carcinomas, usually those containing areas of papillary carcinoma. Alterations in the BRAF gene do not overlap with RAS mutations and RET/PTC rearrangement, indicating that activation of one of the effectors of the MAPK pathway is sufficient for papillary thyroid carcinogenesis. Recently, another mechanism of BRAF activation has been identified, which involves chromosome 7q inversion that results in the AKAP9-BRAF fusion. It is rare in sporadic papillary carcinomas and is more common in tumors associated with radiation exposure. Yet another mechanism of BRAF activation may involve copy number gain, which is seen in a significant portion of thyroid follicular tumors of both conventional and oncocytic (Hürthle cell) types.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186, 1997.

    Article  PubMed  CAS  Google Scholar 

  2. Marais R, Light Y, Paterson HF, Mason CS, Marshall CJ. Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 272:4378–4383, 1997.

    Article  PubMed  CAS  Google Scholar 

  3. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689, 1989.

    PubMed  CAS  Google Scholar 

  4. Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 93:1062–1074, 2001.

    Article  PubMed  CAS  Google Scholar 

  5. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 417:949–954, 2002.

    Article  PubMed  CAS  Google Scholar 

  6. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867, 2004.

    Article  PubMed  CAS  Google Scholar 

  7. 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 63:1454–1457, 2003.

    PubMed  CAS  Google Scholar 

  8. Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95:625–627, 2003.

    Article  PubMed  CAS  Google Scholar 

  9. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580, 2003.

    Article  PubMed  CAS  Google Scholar 

  10. 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 Res 63:4561–4567, 2003.

    PubMed  CAS  Google Scholar 

  11. Fukushima T, Suzuki S, Mashiko M, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene 22:6455–6457, 2003.

    Article  PubMed  CAS  Google Scholar 

  12. Namba H, Nakashima M, Hayashi T, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88:4393–4397, 2003.

    Article  PubMed  CAS  Google Scholar 

  13. 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. J Clin Endocrinol Metab 88:5399–5404, 2003.

    Article  PubMed  CAS  Google Scholar 

  14. Xing M, Vasko V, Tallini G, et al. BRAF T1796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab 89:1365–1368, 2004.

    Article  PubMed  CAS  Google Scholar 

  15. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas. Virchows Arch 444:572–576, 2004.

    Article  PubMed  Google Scholar 

  16. Trovisco V, Vieira de Castro I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 202:247–251, 2004.

    Article  PubMed  CAS  Google Scholar 

  17. Fugazzola L, Mannavola D, Cirello V, et al. BRAF mutations in an Italian cohort of thyroid cancers. Clin Endocrinol (Oxf) 61:239–243, 2004.

    Article  CAS  Google Scholar 

  18. Frattini M, Ferrario C, Bressan P, et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene 23:7436–7440, 2004.

    Article  PubMed  CAS  Google Scholar 

  19. Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH. BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol 17:1359–1363, 2004.

    Article  PubMed  CAS  Google Scholar 

  20. Puxeddu E, Moretti S, Elisei R, et al. BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab 89:2414–2420, 2004.

    Article  PubMed  CAS  Google Scholar 

  21. Lima J, Trovisco V, Soares P, et al. BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 89:4267–4271, 2004.

    Article  PubMed  CAS  Google Scholar 

  22. Kumagai A, Namba H, Saenko VA, et al. Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab 89:4280–4284, 2004.

    Article  PubMed  CAS  Google Scholar 

  23. Nikiforova MN, Ciampi R, Salvatore G, et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 209:1–6, 2004.

    Article  PubMed  CAS  Google Scholar 

  24. Cohen Y, Rosenbaum E, Clark DP, et al. Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid: a potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res 10:2761–2765, 2004.

    Article  PubMed  CAS  Google Scholar 

  25. 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. Am J Clin Pathol 120:71–77, 2003.

    Article  PubMed  CAS  Google Scholar 

  26. Wreesmann VB, Ghossein RA, Hezel M, et al. Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity. Genes Chromosomes Cancer 40:355–364, 2004.

    Article  PubMed  CAS  Google Scholar 

  27. Aldinger KA, Samaan NA, Ibanez M, Hill CS, Jr. Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 41:2267–2275, 1978.

    Article  PubMed  CAS  Google Scholar 

  28. Nishiyama RH, Dunn EL, Thompson NW. Anaplastic spindle-cell and giant-cell tumors of the thyroid gland. Cancer 30:113–127, 1972.

    Article  PubMed  CAS  Google Scholar 

  29. Spires JR, Schwartz MR, Miller RH. Anaplastic thyroid carcinoma. Association with differentiated thyroid cancer. Arch Otolaryngol Head Neck Surg 114:40–44, 1988.

    PubMed  CAS  Google Scholar 

  30. Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H, Samaan NA. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 66:321–330, 1990.

    Article  PubMed  CAS  Google Scholar 

  31. Xing M, Tufano RP, Tufaro AP, et al. Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer. J Clin Endocrinol Metab 89:2867–2872, 2004.

    Article  PubMed  CAS  Google Scholar 

  32. Salvatore G, Giannini R, Faviana P, 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 89:5175–5180, 2004.

    Article  PubMed  CAS  Google Scholar 

  33. Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes. Nat Rev Cancer 4:177–183, 2004.

    Article  PubMed  CAS  Google Scholar 

  34. Pierotti MA. Chromosomal rearrangements in thyroid carcinomas: a recombination or death dilemma. Cancer Lett 166:1–7, 2001.

    Article  PubMed  CAS  Google Scholar 

  35. Ikawa S, Fukui M, Ueyama Y, Tamaoki N, Yamamoto T, Toyoshima K. B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol Cell Biol 8:2651–2654, 1988.

    PubMed  CAS  Google Scholar 

  36. Miki T, Fleming TP, Crescenzi M, et al. Development of a highly efficient expression cDNA cloning system: application to oncogene isolation. Proc Natl Acad Sci USA 88:5167–5171, 1991.

    Article  PubMed  CAS  Google Scholar 

  37. Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115:94–101, 2005.

    Article  PubMed  CAS  Google Scholar 

  38. Edwards AS, Scott JD. A-kinase anchoring proteins: protein kinase A and beyond. Curr Opin Cell Biol 12:217–221, 2000.

    Article  PubMed  CAS  Google Scholar 

  39. Smida J, Salassidis K, Hieber L, et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int J Cancer 80:32–38, 1999.

    Article  PubMed  CAS  Google Scholar 

  40. Rabes HM, Demidchik EP, Sidorow JD, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 6:1093–1103, 2000.

    PubMed  CAS  Google Scholar 

  41. Sachs RK, Chen AM, Brenner DJ. Review: proximity effects in the production of chromosome aberrations by ionizing radiation. Int J Radiat Biol 71:1–19, 1997.

    Article  PubMed  CAS  Google Scholar 

  42. Savage JR. Cancer. Proximity matters. Science 290:62–63, 2000.

    Article  PubMed  CAS  Google Scholar 

  43. Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290:138–141, 2000.

    Article  PubMed  CAS  Google Scholar 

  44. Knauf JA, Ma X, Smith EP, et al. Target expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 65:4238–4245, 2005.

    Article  PubMed  CAS  Google Scholar 

  45. Ciampi R, Zhu Z, Nikiforov YE. BRAF copy number gains in thyroid tumors detected by fluorescence in situ hybridization. Endoc Path 16:99–105, 2005.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

    Raffaele Ciampi PhD &  Yuri E. Nikiforov MD, PhD

Authors
  1. Raffaele Ciampi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuri E. Nikiforov MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuri E. Nikiforov MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciampi, R., Nikiforov, Y.E. Alterations of the BRAF gene in thyroid tumors. Endocr Pathol 16, 163–171 (2005). https://doi.org/10.1385/EP:16:3:163

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/EP:16:3:163

Key Words

Search

Navigation