General information about the study

Modern advances in the treatment of oncological diseases are largely associated with the discovery of the molecular mechanisms of the onset and development of malignant neoplasms, which distinguish them from the cells of normal tissues, and the emergence of drugs that can affect them. Such drugs are called targeted, that is, acting on a specific "target" in the tumor cell. They have a good safety profile, since, in contrast to standard chemotherapy, they practically do not act on normal tissues and are more effective. However, the appointment of targeted drugs is possible only if a specific target for their action is found in tumor cells. In addition, the detection of certain genetic abnormalities in tumor cells can be used as a prognostic factor.

Relatively often, the pathological mechanism of malignant transformation of cells is a defect in the so-called signaling pathways. The signaling pathway is a chain through which an activating signal from a receptor located on the cell surface is transmitted through several intracellular proteins to the nucleus. One of these signaling pathways is MAPK (Mitogen-activated protein kinase). Extracellular signals (growth factors, hormones), by binding to the receptor, activate the MAPK pathway, which in turn leads to the activation of genes responsible for proliferation in the cell nucleus. The MAPK signaling cascade includes proteins of four families: RAS, RAF, MEK, and ERK. RAF is represented by three proteins - ARAF, BRAF, and CRAF, of which BRAF is the most active. Normally, the signaling pathway is activated only through the binding of a receptor to a specific molecule. However, when point mutations occur in genes encoding signaling proteins, they can acquire new properties. Thus, with certain mutations of the BRAF gene, this protein becomes capable of activating the signaling pathway independently of the receptor and triggering the process of uncontrolled cell division.
Mutations of BRAF gene are characteristic of skin melanomas (according to various sources, from 30 to 70%), colorectal cancer, non-small cell lung cancer (about 3%), as well as papillary thyroid cancer. The most common mutation of the BRAF V600E gene, the second in frequency V600K, is much less common V600D and V600R. The letters in the designation of these mutations mean the replacement of a normal amino acid (valine) at the six hundredth position of the protein with another. After the discovery of the role of mutations in BRAF gene in the pathogenesis of tumors, including melanoma, new drugs have been developed - low molecular weight inhibitors of the mutated BRAF enzyme. 
The material for research is DNA of tumor cells. It can be isolated from a biopsy of a tumor in a paraffin block. If a tumor sample is provided for research in a container with a fixing solution, paraffin blocks are made from it for the possibility of long-term storage and subsequent use for other diagnostic tests.

The effect of BRAF inhibitors on tumor cells lacking mutations in the gene of this protein may, on the contrary, be accompanied by pathological activation of the RAS-RAF-MEK-ERK cascade and provoke the growth of melanoma. Therefore, it is extremely important to diagnose the mutational status of BRAF. BRAF inhibitors should not be given in cases where the mutation is not detected or its status is not reliably known.