Clinical and Translational Oncology

, Volume 18, Issue 9, pp 863–871 | Cite as

Braf V600E mutation in melanoma: translational current scenario

  • J. A. Guadarrama-Orozco
  • A. Ortega-Gómez
  • E. B. Ruiz-GarcíaEmail author
  • H. Astudillo-de la Vega
  • A. Meneses-García
  • C. Lopez-Camarillo
Review Article


Melanoma was one of the translational cancer examples in clinic, including target therapy related to specific biomarkers impacting in the outcome of melanoma patients. Melanomagenesis involved a wide variety of mutations during his evolution; many of these mutated proteins have a kinase activity. One of the most cited proteins in melanoma is BRAF (about 50–60 % of melanomas harbors activating BRAF mutations), for these the most common is a substitution of valine to glutamic acid at codon 600 (p.V600E). Therefore, the precise identification of this underlying somatic mutation is essential; knowing the translational implications has opened a wide view of melanoma biology and therapy.


Melanoma BRAF V600E Inhibitor resistance 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Merrill RM, Pace ND, Elison AN. Cutaneous malignant melanoma among white hispanics and non-hispanics in the United States. Ethn Dis. 2010;20(4):353–8.PubMedGoogle Scholar
  2. 2.
    Whiteman D, Green A. Skin cancer—a world-wide perspective. In: Dummer R, Pittelkow MR, Iwatsuki K, Green A, Elwan NM, editors. Berlin, Heidelberg: Springer Berlin Heidelberg; 2011. Accessed 2013 Dec 2.
  3. 3.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. 2012. Accessed 2014 May 20.
  4. 4.
    Wellbrock C, Karasaridis M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Mandalà M, Voit C. Targeting BRAF in melanoma: Biological and clinical challenges. Crit Rev Oncol Hematol [Internet]. Elsevier Ireland Ltd; 2013 Feb 14;1–17. Accessed 2013 Mar 11.
  6. 6.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature [Internet]. 2002 Jun 27;417(6892):949–54.
  7. 7.
    Lohmann JU, Weigel D. Oncogenic mutations in B-Raf. Cell. 2004;116(6):764–6.CrossRefGoogle Scholar
  8. 8.
    Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyrhonen S, et al. BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res [Internet]. 2003;9(9):3362–8.
  9. 9.
    Catalogue of Somatic Mutations in Cancer (COSMIC) at
  10. 10.
    Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, et al. Distinguishing clinicopathologic features of patients with V600E and V600 K BRAF-mutant metastatic melanoma. Clin Cancer Res [Internet]. 2012 Jun 15;18(12):3242–9. Accessed 2015 Jan 5.
  11. 11.
    Wan PTC, 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 [Internet]. 2004 Mar 19;116(6):855–67.
  12. 12.
    Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nat Genet [Internet]. 2003 Jan;33(1):19–20. Accessed 2014 Feb 25.
  13. 13.
    Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol [Internet]. 2005 Feb 8;15(3):249–54. Accessed 2014 Sep 17.
  14. 14.
    Wellbrock C, Karasarides MMR, Wellbrock C, Karasaridis M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875–85.CrossRefPubMedGoogle Scholar
  15. 15.
    Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov [Internet]. 2012 Sep;2(9):791–7. Accessed 2014 Jan 21.
  16. 16.
    Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, et al. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol [Internet]. Springer-Verlag; 2011;122(1):11–9.
  17. 17.
    Long G V, Wilmott JS, Capper D, Preusser M, Zhang YE, Thompson JF, et al. Immunohistochemistry Is Highly Sensitive and Specific for the Detection of V600E BRAF Mutation in Melanoma. Am J Surg Pathol [Internet]. 2013;37(1).
  18. 18.
    Ihle MA, Fassunke J, König K, Grünewald I, Schlaak M, Kreuzberg N, et al. Comparison of high resolution melting analysis, pyrosequencing, next generation sequencing and immunohistochemistry to conventional Sanger sequencing for the detection of p.V600E and non-p.V600E BRAF mutations. BMC Cancer [Internet]. BioMed Central; 2014;14:13.
  19. 19.
    Lee J-H, Choi J-W, Kim Y-S. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol [Internet]. 2011;164(4):776–84. Accessed 2013 Dec 2.
  20. 20.
    Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med [Internet]. 2008;5(6):e120. Accessed 2014 Mar 4.
  21. 21.
    Maldonado JL, Fridlyand J, Patel H, Jain a. N, Busam K, Kageshita T, et al. Determinants of BRAF mutations in primary melanomas. JNCI J Natl Cancer Inst [Internet]. 2003;95(24):1878–90.
  22. 22.
    Kumar R, Angelini S, Czene K, Sauroja I. BRAF mutation in metastasic melanoma: a possible association with clinical outcome. Clin Cancer Res. 2003;9:3362–8.PubMedGoogle Scholar
  23. 23.
    Curtin. Distinct sets of genetic alterations in melanoma. NEJM. 2005;353:2135–47.Google Scholar
  24. 24.
    Boursault L, Haddad V, Vergier B, Cappellen D, Verdon S, Bellocq J, et al. Tumor homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma determined by immunohistochemical and molecular testing. PLoS One [Internet]. 2013;8(8):e70826. Accessed 2013 Dec 18.
  25. 25.
    Heinzerling L, Baiter M, Kühnapfel S, Schuler G, Keikavoussi P, Agaimy A, et al. Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations. Br J Cancer [Internet]. 2013;109(11):2833–41. Accessed 2014 Sep 2.
  26. 26.
    Colombino M, Lissia A, Capone M, De Giorgi V, Massi D, Stanganelli I, et al. Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma. J Transl Med [Internet]. 2013;11(1):202. Accessed 2013 Dec 2.
  27. 27.
    Balint B, Hurk K van den, Toomey S, Unwin L, Sheahan K, McDermott E, et al. Low incidence of BRAFV600E mutation among melanoma patients in Ireland. Cancer Res. 2013;73(8):23.CrossRefGoogle Scholar
  28. 28.
    Saroufim M, Habib R, Karram S, Youssef Massad C, Taraif S, Loya A, et al. BRAF Analysis on a Spectrum of Melanocytic Neoplasms: An Epidemiological Study Across Differing UV Regions. Am J Dermatopathol [Internet]. 2013 18;0(0):1–6.
  29. 29.
    Lazarev I, Yakobson A, Ariad S. BRAF mutations are frequent in malignant melanoma in Israeli population and predicts poor response to biochemotherapy. Ann Oncol. 2012;23(suppl 9):373.Google Scholar
  30. 30.
    Si L, Kong Y, Xu X, Flaherty KT, Sheng X, Cui C. Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort. 2011;8:0–6.Google Scholar
  31. 31.
    Yamazaki N, Tanaka R, Tsutsumida A, Namikawa K, Eguchi H. BRAF V600 Mutations and pathological features in Japanese melanoma. ESMO. 2013.Google Scholar
  32. 32.
    Long G V, 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 [Internet]. 2011;29(10):1239–46. Accessed 2013 Mar 7.
  33. 33.
    Hacker E, Hayward NK, Dumenil T, James MR, Whiteman DC. The association between MC1R genotype and BRAF mutation status in cutaneous melanoma: findings from an Australian population. J Invest Dermatol [Internet]. Nature Publishing Group; 2010;130(1):241–8. Accessed 2013 Apr 17.
  34. 34.
    E. Ruiz-Garcia, A. Meneses, H. Martinez-Said, J.L. Aguilar-Ponce, A. Mohar, A. López, O. Alonso-Luna, J.A. Guadarrama-Orozco, D. Green HA la V. Prevalence of BRAF V600E mutation in metastatic melanoma of Mexican Mestizo population. ECCO-ESMO Cancer Congress. 2013.Google Scholar
  35. 35.
    Ellerhorst J, Greene V, Ekmekcioglu S. Clinicl correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res. 2011;17:229–35.CrossRefPubMedGoogle Scholar
  36. 36.
    Edlundh-Rose E, Egyházi S, Omholt K, Månsson-Brahme E, Platz A, Hansson J, et al. BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res [Internet]. 2006;16(6):471–8.
  37. 37.
    Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483–8.PubMedGoogle Scholar
  38. 38.
    Sigalotti L, Fratta E, Parisi G. Stability of BRAF V600E mutation in metastatic melanoma: new insights for therapeutic success? Br J Cancer. 2011;105:327–8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med [Internet]. 2010;363(9):809–19.
  40. 40.
    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 [Internet]. 2011;364(26):2507–16.
  41. 41.
    Sosman J a, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med [Internet]. 2012;366(8):707–14.
  42. 42.
    Hauschild A, Grob JJ, Demidov L V., Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet [Internet]. Elsevier Ltd; 2012;380(9839):358–65.
  43. 43.
    Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med [Internet]. 2013;19(11):1401–9.
  44. 44.
    Flaherty K, Puzanov I, Kim K. Inhibition of mutated, activated BRAF in metastatic melanoma. … Engl J … [Internet]. 2010;363(9):809–19. Available from: Accessed 2014 Mar 4.
  45. 45.
    Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Bucheit AD, Davies M a. Emerging insights into resistance to BRAF inhibitors in melanoma. Biochem Pharmacol [Internet]. Elsevier Inc.; 2014;87(3):381–9. Accessed 2014 Mar 3.
  47. 47.
    Shi H, Moriceau G, Kong X, Lee M-K, Lee H, Koya RC, et al. Melanoma whole-exome sequencing identifies V600 EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun [Internet]. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2012;3:724.
  48. 48.
    Smalley KSM, Lioni M, Dalla Palma M, Xiao M, Desai B, Egyhazi S, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther [Internet]. 2008;7(9):2876–83. Accessed 2014 Mar 10.
  49. 49.
    Ascierto P, Schadendorf D, Berking C, Agarwala S, van Herpen C, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249.CrossRefPubMedGoogle Scholar
  50. 50.
    Nathanson KL, Martin A-M, Wubbenhorst B, Greshock J, Letrero R, D’Andrea K, et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res [Internet]. 2013;19 (17):4868–78.
  51. 51.
    Paraiso KHT, Xiang Y, Rebecca VW, Abel E V, Chen YA, Munko a C, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res [Internet]. 2011;71(7):2750–60. Accessed 2014 Feb 24.
  52. 52.
    Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature [Internet]. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved; 2012;487(7408):505–9.
  53. 53.
    Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate a J, Settleman J, Engelman J a. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal [Internet]. 2010;3(149):ra84. Accessed 2014 Feb 6.
  54. 54.
    Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature [Internet]. Nature Publishing Group; 2010;468(7326):973–7. Accessed 2014 Mar 19.
  55. 55.
    Villanueva J, Vultur A, Lee JT, Somasundaram R, Cipolla AK, Wubbenhorst B, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by co-targeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683–95.CrossRefPubMedGoogle Scholar
  56. 56.
    Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, et al. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One [Internet]. 2011;6(12):e28973.
  58. 58.
    Omholt K, Karsberg S, Platz A, Kanter L, Ringborg U, Hansson J. Screening of N- ras Codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression 1. 2002;8(November):3468–74.Google Scholar
  59. 59.
    Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res [Internet]. 2006;66(19):9483–91. Accessed 2014 Dec 17.
  60. 60.
    Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature [Internet]. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved; 2010;468(7326):968–72.
  61. 61.
    Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci [Internet]. 2015;36(9):587–95. Accessed 2015 Oct 12.
  62. 62.
    Atefi M, Avramis E, Lassen A, Wong D. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res [Internet]. 2014;20(13):3446–57. Available from: Accessed 2015 Oct 12.
  63. 63.
    Jiang X, Zhou J, Giobbie-Hurder A, Wargo J, Hodi FS. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res [Internet]. 2013 Feb 1;19(3):598–609. Accessed 2015 Sep 15.
  64. 64.
    Massi D, Brusa D, Merelli B, Falcone C, Xue G, Carobbio A, et al. The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAF V600. Ann Oncol [Internet]. 2015;26(9):1980–7. Accessed 2015 Oct 12.

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2016

Authors and Affiliations

  • J. A. Guadarrama-Orozco
    • 1
  • A. Ortega-Gómez
    • 1
  • E. B. Ruiz-García
    • 1
    Email author
  • H. Astudillo-de la Vega
    • 2
  • A. Meneses-García
    • 3
  • C. Lopez-Camarillo
    • 4
  1. 1.Translational Medicine LaboratoryNational Cancer InstituteMexico CityMexico
  2. 2.Laboratory of Translational Cancer Research and Cellular Therapy, Oncology HospitalMedical Center Siglo XXIMexico CityMexico
  3. 3.National Cancer InstituteMexico CityMexico
  4. 4.Genomics Sciences ProgramAutonomous University of Mexico CityMexico CityMexico

Personalised recommendations