V600E

V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600.[1][2] It is a driver mutation in a proportion of certain diagnoses, including melanoma,[3][4] hairy cell leukemia,[5][6] papillary thyroid carcinoma,[7][8] colorectal cancer,[9] non-small-cell lung cancer,[10][11] Langerhans cell histiocytosis,[12] Erdheim–Chester disease (a non-Langerhans-cell histiocytosis) and ameloblastoma.[13]

The mechanism of the mutation is that the negative charge of the acidic glutamic acid residue causes it to be phosphomimetic. This mimics the phosphorylation of the nearby T599 threonine and S602 serine residues in the activation segment of BRAF, which are used to activate the wild type form of the protein. The glutamate residue of the mutant therefore functions to activate BRAF by inhibiting the interaction of the BRAF's glycine rich loop and activation segment, which would ordinarily be inhibitory. The loss of inhibition of BRAF leads to an increase in its basal activity and hence is oncogenic.

Clinical

Vemurafenib, encorafenib, and dabrafenib are approved by the FDA for treatment of metastatic melanomas that express V600E.

References
  1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. (June 2002). "Mutations of the BRAF gene in human cancer" (PDF). Nature. 417 (6892): 949–54. doi:10.1038/nature00766. PMID 12068308.
  2. Ritterhouse LL, Barletta JA (September 2015). "BRAF V600E mutation-specific antibody: A review". Seminars in Diagnostic Pathology. 32 (5): 400–8. doi:10.1053/j.semdp.2015.02.010. PMID 25744437.
  3. Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, et al. (December 2003). "Determinants of BRAF mutations in primary melanomas". Journal of the National Cancer Institute. 95 (24): 1878–90. doi:10.1093/jnci/djg123. PMID 14679157.
  4. Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F (May 2015). "Metastatic melanoma - a review of current and future treatment options". Acta Dermato-Venereologica. 95 (5): 516–24. doi:10.2340/00015555-2035. PMID 25520039.
  5. Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. (June 2011). "BRAF mutations in hairy-cell leukemia". The New England Journal of Medicine. 364 (24): 2305–15. doi:10.1056/NEJMoa1014209. PMC 3689585. PMID 21663470.
  6. Dietrich S, Zenz T (December 2015). "BRAF inhibitor therapy in HCL". Best Practice & Research. Clinical Haematology. 28 (4): 246–52. doi:10.1016/j.beha.2015.10.001. PMID 26614903.
  7. Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, et al. (May 2004). "BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas". The Journal of Clinical Endocrinology and Metabolism. 89 (5): 2414–20. doi:10.1210/jc.2003-031425. PMID 15126572.
  8. Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F (October 2008). "BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study". The Journal of Clinical Endocrinology and Metabolism. 93 (10): 3943–9. doi:10.1210/jc.2008-0607. PMID 18682506.
  9. Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B (January 2006). "BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status". Molecular Cancer. 5: 2. doi:10.1186/1476-4598-5-2. PMC 1360090. PMID 16403224.
  10. Sánchez-Torres JM, Viteri S, Molina MA, Rosell R (June 2013). "BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors". Translational Lung Cancer Research. 2 (3): 244–50. doi:10.3978/j.issn.2218-6751.2013.04.01. PMC 4367599. PMID 25806238.
  11. Rothschild SI (May 2015). "Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK". Cancers. 7 (2): 930–49. doi:10.3390/cancers7020816. PMC 4491691. PMID 26018876.
  12. Badalian-Very G, Vergilio JA, Degar BA, Rodriguez-Galindo C, Rollins BJ (January 2012). "Recent advances in the understanding of Langerhans cell histiocytosis". British Journal of Haematology. 156 (2): 163–72. doi:10.1111/j.1365-2141.2011.08915.x. PMID 22017623.
  13. Kurppa KJ, Catón J, Morgan PR, Ristimäki A, Ruhin B, Kellokoski J, Elenius K, Heikinheimo K (April 2014). "High frequency of BRAF V600E mutations in ameloblastoma". The Journal of Pathology. 232 (5): 492–8. doi:10.1002/path.4317. PMC 4255689. PMID 24374844.


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