How BRAF mutation occurs in human body?

BRAF in general

The BRAF gene is normally located on Chromosome 7 (7q34) and encodes the BRAF protein, a member of mammalian cytosolic serine/threonine kinases, which is involved in cell signaling, growth, and survival. Also importantly, BRAF gene is well known mutation in Melanoma as well as non-small Lung cancer (NSCLC). 

1) BRAF in cancer

In general, the mutation of BRAF gene is commonly found in cancer patients with an 8% and it is known to be found in melanoma (40~50%), thyroid carcinoma (10~70%, based on the histologic classification), colorectal cancer (10%), and rarely in lung cancer (1~5%) respectively. [1]

2) How BRAF mutation is occurred?

RAS family of serine and threonine kinases are known as ARAF, BRAF, CRAF. BRAF is also included in this. While all RAF proteins can phosphorylate MEK (MEK1 and MEK2), BRAF has the strongest activation capacity. While all RAF proteins can phosphorylate MEK (MEK1 and MEK2), BRAF has the strongest activation capacity.

BRAF is involved in mitogen-activated protein kinase (MAPK) signaling pathway and this is also known as the Ras-Raf-MEK-ERK pathway. Upstream of BRAF, growth factor binding to receptor tyrosine kinases (RTKs) at the cell surface leads to phosphorylation of rat sarcoma (RAS) proteins, which then activate BRAF. Signal transduction continues downstream from BRAF to MAPK kinase (MEK, mitogen-activated protein/extracellular signal regulated kinase kinase) 1 and MEK2, and finally to extracellular signal-regulated kinase (ERK), which phosphorylates multiple targets and thus regulates cell proliferation, differentiation, and apoptosis, in response to extracellular stimuli, such as cytokines, growth factors, hormones, and environmental stressors. (Figure 2). 

In normal tissue, the BRAF kinase is generally silenced via negative feedback once the signal has moved on to the next point in the cascade. However, when mutations occur in BRAF, the activation of the RAS–RAF–MEK–ERK pathway will be sustained. This leads to uncontrolled cell growth and proliferation. As a results, it makes BRAF mutations potential oncogenic drivers. [1, 2, 3, 4]

3) How BRAF mutations are classified?

Based on mutation site and their activation pathways, BRAF mutations could be classified in three as shown on the figure3. 

3.1 Class I

This is related to codon 600. BRAF V600 (BRAF Mut) acts as a monomer in an RAS-independent manner (RAS WT) and constitutively activate Extracellular Signal-regulated Kinases (ERK) by phosphorylation. In class II signal transduction involves non-V600 mutant. Strong kinase activation is regulated by dimers of mutant BRAF (BRAF Mut), independently of RAS (RAS WT). Class III is kinase-impaired and consists of BRAF non-600 mutant (BRAF Mut) and CRAF wild type (CRAF WT) as a heterodimer. The signal is transferred downstream in the presents of RAS mutant (RAS Mut). 

Class I mutants including V600E/K/D/R, which occurs in the valine residue at amino acid position 600 of exon 15, promote constitutive activation of MAPK pathway, causing strong activation of BRAF kinase; in addition, this type of mutations often presents high sensitivity to BRAF and MEK inhibitors. 

3.2 Class II

This includes K601, L597, G464, and G469 mutations, are located in the activation segment or P-loop and signal as RAS-independent dimers. 

3.3 Class III

Mutants classified as III occurs in the P-loop, catalytic loop, or DFG motif have impaired BRAF kinase activity; however, the activity of MAPK pathway signaling is enhanced via Raf-1 protooncogene CRAF activation. 

All the class II and III mutations are non-V600 mutations, and BRAF mutations are usually classified as V600 mutations and non-V600 mutations in routine clinical practice. Actually, approximately 50% of BRAF mutations in NSCLC are non-V600 mutations. In addition, class II and III BRAF mutations are sensitive to current BRAF inhibitors; hence, novel-generation BRAF inhibitors warrant being developed. [1,2]

Reference

[1] BRAF-Mutated Non-Small Cell Lung Cancer : Current Treatment Status and Future Perspective. Front. Oncol., 2022, 12: 863043

[2] Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks. Genes, 2020, 11: 1342

[3] Clinical development of BRAF plus MEK inhibitor combinations. CellPress Rev. Trends in Cancer, 2020, 6(9): 797-810

[4] Agents to treat BRAF mutant lung cancer. Drugs in Context., 2019, 8: 212566

[5] Precision Cancer Medicines & Immunotherapy for Lung Cancer, CancerConnect News, 2021

https://news.cancerconnect.com/lung-cancer/precision-cancer-medicines-immunotherapy-for-lung-cancer

[6] BRAF Alterations as Therapeutic Targets in Non–Small-Cell Lung Cancer, Jour. of Thoracic Oncol. 2015. 10(10): 1396-1403

[7] Biomarker BRAF. My Cancer Genome

https://www.mycancergenome.org/content/gene/braf/