BRAF Gene Mutation

A mutation in the BRAF gene can lead to uncontrolled cell growth and the development of cancer in various organs throughout the body. Understanding whether your cancer has this genetic change is important because it can guide doctors toward the most effective treatment options for you.

Table of contents

• What is the BRAF gene and what does it do?
• How BRAF mutations develop
• Types of cancers linked to BRAF mutations
• The V600E mutation
• How BRAF mutation status is tested
• What a BRAF mutation means for treatment
• BRAF mutations in colorectal cancer
• BRAF mutations in melanoma
• BRAF mutations in lung cancer
• Other conditions related to BRAF gene changes

What is the BRAF gene and what does it do?

The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell’s nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions^[1].

Specifically, the RAS/MAPK pathway regulates the growth and division of cells (a process called proliferation), the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth^[1].

The BRAF gene encodes the B-raf protein, which plays an important role in controlling cell growth, cell proliferation, and cell differentiation. Cell growth is an increase in cell size, cell proliferation is an increase in the number of cells, and cell differentiation is the process in which immature (unspecialized) cells become mature (specialized) cells^[3].

How BRAF mutations develop

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous^[1].

If the BRAF gene has a mutation, the control system (signaling pathway) for these processes may not function properly. This can allow cells to grow abnormally and become cancer. Genes, like BRAF, that can cause normal cells to become tumor cells are called oncogenes^[3].

The BRAF mutations found in colorectal cancer are somatic, which means they occur in non-reproductive cells and are not hereditary^[3]. A somatic mutation occurs during a person’s lifetime and is present only in certain cells, not in all cells of the body^[1].

BRAF mutations can induce cellular alteration and malignant transformation. Development of many types of cancer is associated with mutations in the BRAF gene. The encoded protein is a component of the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway, transmitting information from the outside to the cell nucleus^[2].

Types of cancers linked to BRAF mutations

The BRAF oncogene plays a role in several different cancers. BRAF mutations are present in approximately 10%-15% of colorectal cancers, 35% of melanomas, and more than 50% of thyroid papillary carcinomas^[3].

In colorectal cancer, the incidence of BRAF mutation is higher in right-sided (proximal) colon cancers compared to left-sided (distal) colon cancers and rectal cancers^[3].

In lung cancer, the BRAF mutation occurs in about 3% to 5% of all non-small cell lung cancers (NSCLC), making it a rare type. It’s found almost exclusively in the adenocarcinoma subtype, which starts in the outer areas of the lung^[10].

The V600E mutation

The most common mutations in the BRAF gene encode the V600E mutant, which causes continuous activation and signal transduction, regardless of external stimulus. Consequently, cell proliferation and invasion are enhanced in cancer patients with such mutations^[2].

This mutation replaces the amino acid valine with the amino acid glutamic acid at position 600 (written as Val600Glu or V600E). This mutation leads to production of a BRAF protein that is abnormally active, which disrupts regulation of cell proliferation^[1].

The majority of BRAF mutations are V600E mutations. Other mutations in BRAF do occur but they are rare^[3].

In non-small cell lung cancer, though several mutations can occur within the BRAF gene, the most common one is BRAF V600E^[17]. In melanoma, an estimated 50% of people have melanomas with a BRAF V600 mutation^[8].

How BRAF mutation status is tested

The recommended method of testing for BRAF mutation status is with a biopsy sample of cancer cells, either from the primary tumor or from tumor metastases (cancer that has spread) in another part of the body, such as lymph nodes, liver, or the lining of the abdomen^[3].

The cancer cells are treated in a laboratory to isolate the tumor DNA to be studied. BRAF may also be tested in a blood sample by examining circulating tumor DNA (ctDNA) for BRAF mutations. This is called a liquid biopsy^[3].

BRAF may be tested individually, or as part of a multi-gene panel using next-generation sequencing (NGS). BRAF mutation testing is sometimes also called BRAF mutation analysis or BRAF gene sequencing^[3].

The presence of the mutation may mean you will be eligible for targeted treatment options. Finding the mutation can also help your healthcare team determine the best treatment for you after diagnosis^[17].

What a BRAF mutation means for treatment

BRAF is both a prognostic factor and a predictive biomarker. BRAF mutation status gives information about the usual course of disease (prognosis) and it predicts which treatments may be more or less effective against a particular cancer^[3].

If your result is reported as “BRAF wild-type” or “BRAF WT”, this means there is no BRAF mutation in your cancer^[3]. If a BRAF mutation is present, it may affect which treatments are recommended for you.

The Food and Drug Administration (FDA) has approved certain medications to treat cancers with specific BRAF mutations^[17].

BRAF mutations in colorectal cancer

All patients with stage IV or metastatic colorectal cancer should have BRAF biomarker testing. The BRAF gene mutates early in the development of cancer and signals certain cells to grow uncontrollably^[7].

Colorectal cancer with wild-type (non-mutant) BRAF may be treated with EGFR inhibitors. Colorectal cancer with BRAF mutations can be treated with targeted therapy, specifically BRAF inhibitors plus MEK inhibitors^[3].

Activating BRAF mutations occur in approximately 5–10% of metastatic colorectal cancer patients, mostly V600E mutation, and it is associated with distinct clinical and pathological features. To date, there are no approved treatments to target this mutation as a single treatment. BRAF inhibitor monotherapy has limited effectiveness in metastatic colorectal cancer, in contrast to metastatic melanoma^[9].

Combination strategies that block not only BRAF mutated kinase but other alternative pathways are ongoing and have demonstrated improved activity^[9].

BRAF mutation tumors have been associated with female gender, advanced age, proximal colon tumor location, poor differentiation, defective mismatch repair tumors and serrated adenoma pathway. They have poor prognosis and typically do not respond well to standard therapy with approximately 12 months of median survival^[9].

BRAF mutations in melanoma

Approximately 50% of all melanomas harbor an activating BRAF mutation. In patients suffering from an advanced melanoma with such a somatic alteration, combined targeted therapy with a BRAF and MEK inhibitor can be applied to significantly increase the survival probability^[16].

A landmark overall survival rate of 34% after 5 years of combined targeted therapy in treatment-naïve patients was reported. On the other hand, patients harboring a BRAF mutation and receiving first-line immune checkpoint blockade with ipilimumab plus nivolumab showed a 5-year overall survival rate of 60%^[16].

Results from a large study called DREAMseq tested initially giving patients a combination of the immunotherapy drugs ipilimumab (Yervoy) and nivolumab (Opdivo) or a combination of the targeted therapies dabrafenib (Tafinlar) and trametinib (Mekinist). More of the patients treated first with immunotherapy drugs were alive at 2 years compared to patients treated first with the targeted therapy combination (72% versus 52%)^[8].

The V600E mutation has been found to cause giant congenital melanocytic nevus. This condition is characterized by a large, noncancerous patch of abnormally dark skin that is present from birth and an increased risk of melanoma. In this condition, a somatic V600E mutation occurs during embryonic development in cells that will develop into pigment-producing skin cells (melanocytes)^[1].

BRAF mutations in lung cancer

BRAF mutations are reported in about 3–5% of non-small-cell lung cancer (NSCLC), almost exclusively in adenocarcinoma histology, and are classified into three different classes. The segmentation of BRAF mutations into V600 (class 1) and non-V600 (classes 2 and 3) relies on their biological characteristics and is of interest for predicting the therapeutic benefit of targeted therapies and immunotherapy^[10].

The BRAF mutation in lung cancer means that your cancer started due to a change in the BRAF gene. It may affect your treatment options and outlook. BRAF proteins and MEK proteins help control the growth and spread of healthy cells. The BRAF mutation occurs in the gene and causes the creation of defective BRAF proteins. When this happens, it can lead to uncontrolled cell growth and cancer^[17].

The BRAF mutation can act as a biomarker in lung cancer. This means that the presence of abnormal BRAF mutations in a biopsy or blood work can indicate the presence of lung cancer. Finding the mutation can also help your healthcare team determine the best treatment for you after diagnosis^[17].

Other conditions related to BRAF gene changes

BRAF gene mutations are also associated with several other health conditions beyond cancer.

Mutations in the BRAF gene are the most common cause of cardiofaciocutaneous syndrome. This condition affects many parts of the body, particularly the heart, facial features, and the skin and hair. At least 49 BRAF mutations have been identified in people with this disorder. These mutations change single protein building blocks in the BRAF protein. Almost all of these genetic changes abnormally activate the protein, which disrupts the tightly regulated RAS/MAPK signaling pathway in cells throughout the body^[1].

At least one mutation in the BRAF gene has been identified in some people with Erdheim-Chester disease. This rare condition is characterized by the abnormal production and accumulation of immune system cells called histiocytes in many of the body’s tissues. The disease most commonly affects the bones, causing bone thickening and pain, but the accumulation of histiocytes can also cause signs and symptoms affecting the brain, eyes, lungs, liver, kidneys, and other organs^[1].

At least two mutations in the BRAF gene have been found to cause Noonan syndrome with multiple lentigines^[1].