BRAF gene
The BRAF gene is a critical component of the RAS/MAPK signaling pathway, responsible for transmitting signals from outside the cell to its nucleus. As an oncogene, BRAF plays a significant role in cell growth, survival, differentiation, and apoptosis. It consists of 766 amino acids and is located on chromosome 7. BRAF mutations, particularly the common V600E mutation, are implicated in various cancers, including malignant melanoma, colorectal cancer, ovarian cancer, and thyroid cancer, leading to uncontrolled cell proliferation. Additionally, mutations in BRAF are associated with cardiofaciocutaneous syndrome, a rare genetic condition characterized by distinctive physical features and developmental challenges. The identification of BRAF mutations has important implications for cancer prognosis and treatment, with ongoing research exploring targeted therapies, particularly BRAF inhibitors, which have shown effectiveness against tumors harboring specific mutations. As advancements continue in genetic testing and targeted therapies, the potential for improved management of diseases related to BRAF mutations is promising.
BRAF gene
SIGNIFICANCE: The BRAF gene is part of the tightly regulated RAS/MAPK pathway and instructs protein development that transmits chemical signals from outside the cell to the nucleus of the cell. BRAF is an oncogene, and mutations in BRAF are evident in cancers and other syndromes. As part of the RAS/MAPK pathway, it contributes to cell activities related to growth, proliferation, differentiation, survival, and apoptosis.
The BRAF Gene
A gene is a subunit of DNA that carries specific instructions for cells, with approximately 25,000 genes in the human body. BRAF is the gene symbol for v-raf murine sarcoma viral homolog B1. The BRAF gene is expressed in most tissues, especially neuronal tissue. It belongs to the oncogene class of genes, contains 766 amino acids, has a molecular weight of 84436 daltons, and is located on chromosome 7 at position 34, or more specifically, from base pair 140,080,750 to base pair 140,271,032 on chromosome 7. As a serine/threonine kinase in the RAS/RAF/MEK/ERK/MAPK pathway, BRAF relays mitogenic signals to the nucleus of the cell from the cell membrane. A normal BRAF gene switches on and off to deliver appropriate proteins necessary in the cell cycle of growth and development. Within the MEK/ERK pathway, it assumes an antiapoptotic role necessary to regulate cell death. A mutation in a gene may be caused by environmental exposures, or it can occur if a mistake is made during cell division. The most common BRAF mutation is V600E, a mutation at T1799A that represents 80 percent of BRAF mutations.
Implications of BRAF Mutation
Somatic mutations in the BRAF gene, or noninherited changes in the body’s cells during an individual’s lifetime, are seen in several cancers. A of BRAF leads to an overexpression of protein that interferes with the normal cell cycle, which may lead to the overactive cell growth evident in the development of cancer. The most common cancers demonstrating a mutation in BRAF include malignant melanoma (70 to 80 percent), colorectal cancer (5 to 40 percent, depending on the mutation), ovarian cancer (approximately 30 percent of low-grade serous tumors), and thyroid cancer (a V600E mutation evident in half of cases). Breast and lung cancers show BRAF mutations, but in fewer cases. BRAF testing provides information related to prognosis, particularly in colorectal and metastatic colorectal cancers.
Cardiofaciocutaneous syndrome is an extremely rare, autosomal dominant condition that results from gene mutations, with approximately 75 percent of cases caused by mutation in the BRAF gene. A rough estimate of the incidence of the condition is two to three hundred cases worldwide. The disorder is caused by overactive expression of protein resulting in alterations in cell communication during development of the fetus. Individuals with cardiofaciocutaneous syndrome have a variety of body changes including heart defects; distinctive facial features with a high forehead, a short nose, droopy eyelids and down-slanting eyes, and low ear placement on the head; a large head, known as macrocephaly; dry, rough skin with small bumps, known as keratosis pilaris; and thin or missing hair, eyebrows, and eyelashes. At birth, infants exhibit poor muscle tone and failure to thrive because of feeding problems, resulting in a lack of growth and weight gain, and they may have seizures. Cancer is not usually seen in relationship to this syndrome.
Future Efforts Related to BRAF
Because identifiable mutations of the BRAF gene may be associated with specific cancers, testing for BRAF mutations holds promise in cancer treatment, and commercial applications are being developed. Studies are being conducted that attempt to measure BRAF mutations and their relationship to clinical tumor stages in an attempt to define prognostic factors and, eventually, treatment strategies. Gene testing is reliable and inexpensive, and is likely to become a standard of care in some cancers.
Studies indicate that BRAF positive tumors may be more sensitive to certain drugs. Three BRAF inhibitors have been approved for use, as have five combinations of a BRAF inhibitor and another agent to manage some cancers. These regimens have been effective against tumors with BRAFV600 mutations.
The V600E has been shown to be sensitive to treatment in laboratory studies through inhibition of the kinase in select melanoma cell lines, leading to cell death. Investigation into the management of BRAF mutations holds promise for therapeutic interventions in multiple diseases and syndromes.
Key terms
- amino acidsform the structure of proteins in the body
- apoptosiscell self-destruction
- differentiationa cell’s ability to develop a more specialized function
- gene mutationa permanent change in the sequence of DNA
- missense mutationintroduction of an incorrect amino acid into a protein
- oncogenemutations in normal cellular genes
- proteinsmade up of amino acids, provide or support almost all chemical processes in cells
- RAS/MAPK pathwaycontrols cellular proliferation and differentiation
- somatic mutationa noninherited change in genetic structure that is not passed to offspring
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