Introduction:
The BRAF protein, which has 766 amino acids, is encoded by the BRAF proto-oncogene (BRAF) gene found on chromosome (7q34) in the human genome. While all RAF proteins can phosphorylate MEK (MEK1 and MEK2), BRAF has the greatest ability for activation. As a result, in response to extracellular stimuli like cytokines, growth factors, hormones, and environmental stressors, the Ras-Raf-MEK-ERK signaling pathway—also known as the Ras-Raf-MAPK/ERK signaling pathway—is stimulated and subsequently controls cell proliferation, differentiation, and apoptosis. It is also known that activation of the Raf-MEK-ERK pathway increases the expression of several target genes. MEK causes ERK (ERK1 and ERK2) to become activated in the cytoplasm and go into the nucleus of cells. Many transcription factors are phosphorylated in the nucleus to activate ERK1/2. Many kinds of cancer are linked to dysregulation in the MAPK/ERK cascade brought on by mutations in the proteins that make up this pathway, including RAS (KRAS and NRAS) and RAF (BRAF).
How Is BRAF Described?
The gene BRAF on chromosome 7 produces a protein with the same name. This protein promotes cell division, among other tasks inside the cell, contributing to cell development.
Three substantially conserved domains of BRAF (CR1, CR2, and CR3). The regulatory regions CR1 and CR2 are found at the protein's N-terminus. The RAS-binding domain (RBD), which interacts with RAS, and the cysteine-rich domain (CRD), which binds two zinc ions, are both included in CR1. CR2 has a 14-3-3 binding site and is a serine/threonine-rich domain. A kinase domain on the C-terminal of CR3 controlled by phosphorylation is present. Two parts of the BRAF kinase domain stand out: a small N-terminal lobe and a large C-terminal lobe.
What Is BRAF Mutation?
A spontaneous change in the BRAF gene that causes it to function wrongly is known as a BRAF mutation. A mutation makes the gene activate the protein and keep it active, which results in some cells receiving constant impulses to divide and no guidance on when to stop. A tumor may form as a result of this.
BRAF mutations come in many different forms, according to researchers. The BRAF V600E mutation is one of the most prevalent varieties. The nature and characteristics of the V600E and the mutation's site are well demonstrated.
The letters V and E represent the mutant amino acids (proteins). In this instance, glutamic acid (GA) took the place of valine (V) (E).
The amino acid number 600 in the protein is where the mutation occurred, hence the number 600.
Various targeted medicines may respond differently to different BRAF mutations. Some BRAF mutations are resistant to specific targeted treatments.
What Is the Connection Between Cancer and the BRAF Mutation?
When combined with other mutations or external conditions, specific BRAF mutations can result in cancer. BRAF mutations, either by themselves or in conjunction with other mutations, can also accelerate the growth of malignancies.
The malignancies linked to the BRAF gene mutation do not only affect one area of the body or one kind of cell. These tumors consist of:
Melanoma (approximately half of all melanomas have the BRAF gene mutation) (about half of all melanomas have the BRAF gene mutation)
-
Hairy cell cancer.
-
Nodular lymphoma.
-
Thyrotoxic cancer.
-
Asbestosis of the lungs.
-
Intestinal cancer.
-
Glioblastoma, pilocytic astrocytoma, and pediatric low-grade glioma are some types of brain cancer.
Is the BRAF Mutation Inherited?
A BRAF mutation linked to cancer typically appears at some point throughout a person's lifetime. In this case, the mutation affects the cells where the alteration occurred and cannot be passed on to the children. BRAF mutations are uncommon to inherit (passed on from a parent). A mutation that is present at birth may have an impact on many bodily cells and result in serious health problems.
How to Undergo a BRAF Mutation Test?
The oncologist could advise examining the tumor's DNA to determine whether it carries a BRAF mutation if one have a malignancy. Through a biopsy, a tumor tissue sample will be collected and sent to a laboratory for genetic analysis. The test findings will indicate the kind of mutation and whether the sample has the BRAF mutation. Because of the position of some tumors, it may not always be possible to do a biopsy, which is a surgical procedure.
The doctor might suggest a blood test if a biopsy is not possible. It is speedier and less intrusive but only detects specific BRAF mutations and provides less information than a genetic test.
If one does not have a tumor but is eligible for testing because of a family history of the disease or other risk factors that make the doctor suspect a BRAF mutation, one may be able to have a BRAF blood test.
What Are the BRAF-Mutated Tumor Treatments?
Scientists have created specific drugs called BRAF inhibitors that block the way the B-Raf protein tells cells to divide and expand due to a greater understanding of the role of the BRAF gene in tumor growth. Although it does not eliminate cancer cells, it does assist in temporarily reducing the growth of tumors. Dabrafenib, Encorafenib, and Vemurafenib are a few BRAF inhibitors that have been authorized for treatment in specific tumor types.
Combined Therapies
The RAS-RAF-MEK-ERK pathway is a more extensive system that includes the B-Raf protein. This route aids in controlling how cells divide, proliferate, and survive. Any hyperactive portion of this pathway inside a tumor aids the growth and probable spread of the malignancy.
BRAF inhibitors alone can be effective in treating some cancers. In other circumstances, your oncologist could advise combining a BRAF inhibitor with one or more medications that block the RAS-RAF-MEK-ERK pathway. BRAF inhibitors are frequently used with MEK inhibitors that target a different portion of the path, such as Trametinib, Binimetinib, Selumetinib, or Cobimetinib.
BRAF and MEK inhibitors can occasionally be used with immunotherapy. With immunotherapy, the immune system is activated to fight cancer. Immune checkpoint inhibitors, a type of immunotherapy, function by assisting the immune system to attack the tumor cells. The immune system contains methods to regulate how forcefully it reacts to threats, preventing healthy cells from suffering damage in the process. By disabling this pathway, checkpoint inhibitors can enhance the immune system's response to the tumor.
Conclusion:
BRAF mutations in the kinase activation region significantly modify the MAPK/ERK signaling pathway. These mutations have different clinical effects depending on the locus. Information from external stimuli is not linearly sent to the cell nucleus through the MAPK/ERK pathway. Deciphering the molecular mechanisms causing signal transmission modifications in the context of a particular mutation is vital. To inform individualized anti-cancer treatment, molecular studies, such as RNA sequencing, should be carried out to detect aberrant gene expressions and transcriptional networks in the presence of various BRAF mutations. These cutting-edge treatments should target particular mutations and their consequences in this regard.
