The BRAF gene provides instructions for a protein that helps manage important cell functions, particularly those related to growth. When this gene undergoes a mutation, it can malfunction, sending continuous signals for cells to divide uncontrollably. This unchecked cell proliferation can lead to the formation of tumors and the development of various cancers.
Understanding the BRAF Gene and Its Mutation
The BRAF gene is located on chromosome 7 and produces the BRAF protein. This protein is a component of the RAS/MAPK signaling pathway, which is a complex network inside cells that regulates essential functions like cell growth, division, differentiation, and survival. Normally, the BRAF protein acts like a switch, turning on and off to transmit signals that control the cell cycle.
A gene mutation represents a permanent change in the DNA sequence. In the context of BRAF, a mutation can cause the protein to be constantly “on,” leading to continuous signaling for cell division even without external cues. The most common BRAF mutation is known as V600E. This specific alteration involves a change at amino acid position 600, where valine (V) is replaced by glutamic acid (E).
The V600E mutation leads to a hyperactive BRAF protein, which continuously stimulates the downstream MEK/ERK pathway. The mutation essentially bypasses the normal regulatory mechanisms that would typically halt cell division, allowing abnormal cells to multiply without restraint.
Cancers Associated with BRAF Mutations
BRAF mutations are found in a range of cancers, with varying prevalence across different types. Melanoma, a type of skin cancer, has the highest rate of BRAF mutations, occurring in approximately 50% of cases, with the V600E variant accounting for most of these mutations. These mutations are more common in younger patients and in melanomas not linked to chronic sun exposure.
BRAF mutations are also relevant in colorectal cancer, where they are present in about 10% to 15% of cases. The V600E mutation is the most common BRAF alteration in colorectal cancer. These mutations are often associated with right-sided primary tumors, mucinous histology, and a poorer prognosis.
Thyroid cancer, particularly papillary thyroid carcinoma (PTC), also frequently harbors BRAF mutations. The estimated occurrence of BRAF mutations in PTC patients can range from 29% to 83%, with the V600E mutation being the most prevalent. Additionally, BRAF mutations are found in a smaller percentage of non-small cell lung cancer (NSCLC) cases, typically between 1.5% and 4%. Approximately 50% of BRAF mutations in NSCLC are non-V600 mutations.
Identifying BRAF Mutations
Genetic testing for BRAF mutations plays a significant role in cancer diagnosis and treatment planning. Identifying these mutations helps determine if a patient might benefit from specific targeted therapies. Testing is typically performed on tumor tissue obtained through a biopsy.
Common methods for detecting BRAF mutations include polymerase chain reaction (PCR), Sanger sequencing, and next-generation sequencing (NGS). PCR-based tests offer faster results and better reproducibility. Sanger sequencing can detect point mutations and small insertions or deletions, but its sensitivity may be limited in samples with a low percentage of tumor cells. NGS provides comprehensive genetic profiling and can identify a broader range of mutations.
In situations where a tissue biopsy is challenging or not feasible, liquid biopsy offers a less invasive alternative. This method involves analyzing circulating tumor DNA (ctDNA) from blood samples. Liquid biopsies can detect BRAF mutations in patients with advanced cancers, and studies have shown good concordance, often over 80%, between liquid biopsy and traditional tissue biopsy results.
Treating BRAF-Mutated Cancers
Targeted therapies have revolutionized the treatment of cancers with BRAF mutations by specifically blocking the activity of the mutated protein or its downstream signaling pathway. BRAF inhibitors, such as vemurafenib, dabrafenib, and encorafenib, directly target the mutated BRAF protein, halting its continuous signaling.
Combining BRAF inhibitors with MEK inhibitors has become a standard treatment approach for many BRAF-mutated cancers, particularly advanced melanoma. MEK inhibitors, including trametinib, cobimetinib, and binimetinib, block another protein in the same signaling pathway, MEK, which is downstream of BRAF. This dual inhibition improves treatment efficacy, delays the development of resistance, and can reduce some side effects associated with BRAF inhibitor monotherapy, such as certain skin issues.
For instance, in BRAF V600-mutant melanoma, combinations like dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib have demonstrated improved progression-free survival and overall survival compared to single-agent therapies. These combination regimens have significantly altered patient outcomes, offering effective control over the disease in a subset of patients who previously had limited options. The long-term benefits of these therapies have been observed, with a notable percentage of patients achieving durable responses extending for several years.