BRAF gene and cancer

ALSO KNOWN AS: BRAF1, RAFB1, proto-oncogene B-Raf, v-raf murine sarcoma viral oncogene homolog B1

DEFINITION: BRAF is an internal part of a cellular signaling pathway. This signaling pathway results in cell growth when the correct chemical message is sent. The mutated form of the BRAF gene has a single base (letter) of deoxyribonucleic acid (DNA) changed, which changes the activity of the BRAF protein. This mutant BRAF protein is broken and is continuously on, sending growth signals even when there are no chemical messages. This continuous signal causes runaway growth of cells. The result is like a broken light switch that will not turn off.

Etiology and symptoms of associated cancers: Mutated BRAF proteins cause many types of cancer, including melanoma, colon cancer, ovarian cancer, thyroid cancer, and gliomas. Knowledge of the BRAF gene, which was first described as a proto-oncogene in 2002, is useful in diagnosing cancer and deciding what type of treatment is necessary.

Tumors are either "" (not harmful) or "" (harmful). Benign tumors can acquire mutations that change them into malignant cancers. Experts believe that cancer requires multiple steps to form. Many normal functions of cells need to be damaged to create a malignant cancer. Cellular functions typically damaged are cell growth (unregulated cell growth), telomere maintenance (cell aging), apoptosis (cell death), angiogenesis (the ability to grow blood vessels), and metastasis (the ability of cells to detach from one part of the body and migrate to another).

BRAF mutations primarily affect the first of these functions, which is cell growth. When BRAF is mutated in a cell, the cell receives a continuous signal to grow and divide. This signal from BRAF also has a smaller effect of reducing the probability of cells dying by apoptosis, an effect promoting metastasis, and effects promoting angiogenesis. BRAF mutations are often found in benign growths.

Mutations of other genes are needed to destroy the remaining cell functions and make a growth malignant. For example, the destruction of the TP53 gene (also known as p53) will help the cancer overcome cell aging (which normally slows down the overgrowing cells) and apoptosis (which normally kills off some of the overgrowing cells). For comparison, TP53 mutations are rarely found in benign growths and are almost always found as secondary changes in cancers.

Because BRAF mutations are found in benign and malignant growths, many people believe BRAF is an early change that eventually leads to malignant cancers. Cancers that seem to begin with BRAF mutations also seem to end up being among the most malignant. Even though BRAF is associated with the worst types of malignancies, the silver lining is that since BRAF mutations happen early, while the tumors are still benign, the BRAF mutation can serve as an early warning sign.

BRAF mutation is not found in all cancer, but only in cancers of certain tissues. Most of these tissues are what doctors call "adenoid tissues." Specifically, BRAF mutation has been found in (skin), glioma (nerve), thyroid, ovarian, and colon cancer.

Researchers have shown that about 50 percent of malignant melanomas studied carried the BRAF mutation, and more than 80 percent of the benign nevi (moles) studied carried the BRAF V600E mutation, as reported by Cancers in 2023 and the Iranian Journal of Pathology in 2020, respectively. In benign gliomas, BRAF mutation is rarely observed, but in malignant gliomas, the BRAF mutation was almost always observed.

Testing and treatment: Standard tests of DNA can be done on blood or tumor tissue samples to detect the BRAF mutation. While these tests are very reliable, the knowledge of the BRAF gene mutation and the tests for it are new and are not yet widely available. BRAF mutation tests will help doctors determine the exact type of cancer, how dangerous it is, and what types of treatment to use.

In 2011, the US Food and Drug Administration (FDA) approved the first targeted therapy drug for melanoma patients with BRAF gene mutations, vemurafenib (Zelboraf). Vemurafenib targets the most common BRAF mutation, V600E, and is used in patients with metastatic melanoma. The American Cancer Society reported in October 2013 that using a BRAF inhibitor such as vemurafenib or dabrafenib (Tafinlar) alone had been found to increase the risk of a secondary skin cancer, squamous cell carcinoma, but that using dabrafenib and the MEK inhibitor trametinib (Mekinist) in combination could block both skin cancer pathways. As of May 2014, dabrafenib was in clinical trials for the treatment of BRAF-related thyroid cancer, especially radioactive iodine-resistant thyroid cancer, as reported by the American Society for Clinical Oncology. In 2015, Thyroid: Official Journal of the American Thyroid Association demonstrated success in treating such patients, citing a 29 percent response rate, with 64 percent of patients achieving at least a 10 percent reduction in tumor size.

In 2022, the FDA approved a dabrafenib–trametinib (Mekinist) combination, which expanded the number of treatments approved for a larger number of tumors and cancers througout the body. This allows for more patients to be treated for BRAF mutations.

History: The discovery of the BRAF mutation is a direct result of the Human Genome Project. In the 1990s, the Human Genome Project sequenced the human genome and described the complete set of about thirty thousand human genes, the instructions for the body. In the 2000s, the Cancer Genome Project started examining all thirty thousand genes in cancers to find broken genes. One result was the discovery of the BRAF gene mutation in 2002.

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