Biology: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
- ↑ "Mutations of the BRAF gene in human cancer". Nature 417 (6892): 949–54. June 2002. doi:10.1038/nature00766. PMID 12068308. http://eprints.gla.ac.uk/121/1/Davis%2CH_2002_pdf.pdf.
- ↑ "BRAF V600E mutation-specific antibody: A review". Seminars in Diagnostic Pathology 32 (5): 400–8. September 2015. doi:10.1053/j.semdp.2015.02.010. PMID 25744437.
- ↑ "Determinants of BRAF mutations in primary melanomas". Journal of the National Cancer Institute 95 (24): 1878–90. December 2003. doi:10.1093/jnci/djg123. PMID 14679157.
- ↑ "Metastatic melanoma - a review of current and future treatment options". Acta Dermato-Venereologica 95 (5): 516–24. May 2015. doi:10.2340/00015555-2035. PMID 25520039. http://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=4849&context=open_access_pubs.
- ↑ "BRAF mutations in hairy-cell leukemia". The New England Journal of Medicine 364 (24): 2305–15. June 2011. doi:10.1056/NEJMoa1014209. PMID 21663470.
- ↑ "BRAF inhibitor therapy in HCL". Best Practice & Research. Clinical Haematology 28 (4): 246–52. December 2015. doi:10.1016/j.beha.2015.10.001. PMID 26614903.
- ↑ "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. May 2004. doi:10.1210/jc.2003-031425. PMID 15126572.
- ↑ "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. October 2008. doi:10.1210/jc.2008-0607. PMID 18682506.
- ↑ "BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status". Molecular Cancer 5: 2. January 2006. doi:10.1186/1476-4598-5-2. PMID 16403224.
- ↑ "BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors". Translational Lung Cancer Research 2 (3): 244–50. June 2013. doi:10.3978/j.issn.2218-6751.2013.04.01. PMID 25806238.
- ↑ "Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK". Cancers 7 (2): 930–49. May 2015. doi:10.3390/cancers7020816. PMID 26018876.
- ↑ "Recent advances in the understanding of Langerhans cell histiocytosis". British Journal of Haematology 156 (2): 163–72. January 2012. doi:10.1111/j.1365-2141.2011.08915.x. PMID 22017623.
- ↑ "High frequency of BRAF V600E mutations in ameloblastoma". The Journal of Pathology 232 (5): 492–8. April 2014. doi:10.1002/path.4317. PMID 24374844.
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