(BRAF V600E)

BRAF - B-Raf proto-oncogene – is a gene encoding a protein belonging to the RAF family of serine/threonine protein kinases. The protein takes part in regulation of the MAP kinase/ERK signaling pathway, which affects cell division and differentiation. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, but it has also been identified in other cancers as well, including hairy cell leukemia, colorectal carcinoma, thyroid carcinoma and non-small cell lung carcinoma. 


IHC for BRAF V600E mutations can be used as a surrogate for molecular analysis e.g. using RT-PCR. Several publications have shown high concordance between IHC and molecular testing indicating overall agreement of 95-99% between the two different methods. The majority of BRAF mutations occur at amino acid V600, with the V600E mutation most prevalent. Other mutations as V600K, V600M, V600R, V600D and V600G are less common. The BRAF V600E mutation is detected in approximately 8% of all solid tumours, including 100% of hairy cell leukemia, 45% of papillary thyroid carcinomas, 40–60% of melanomas, 5–15% of colorectal adenocarcinomas and 1–3% of non-small cell lung cancers. 

IHC for BRAF V600E is both used as predictive biomarker for BRAF inhibitors as vemurafenib and dabrafenib in melanoma but also as a biomarker to distinguish between hereditary (Lynch) and sporadic MMR deficient colon adenocarcinoma, as BRAF mutations are virtually absent in hereditary colon adenocarcinomas and seen in up 60% of sporadic colon adenocarcinomas.


Tumors confirmed with and without BRAF V600E mutation are recommended as positive and negative tissue controls for BRAF. Appendix can also serve as a negative tissue control, where no staining reaction should be seen in the epithelial cells. At present, no data is available on consistent low-level expressing normal tissues/cells, and thus it is important to secure distinct and an “as strong as possible reaction” for BRAF in mutated tumors and still no reaction in negative tissue controls.

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