A BRAF fusion is a genetic alteration found in the DNA of some cancer cells. It involves the BRAF gene, which helps control cell growth, breaking apart and reattaching to a piece of a different gene to create a hybrid gene. The presence of a BRAF fusion can directly drive tumor growth. It also represents a specific vulnerability in cancer cells that can be attacked with targeted drug therapies, offering a more precise treatment compared to traditional chemotherapy.
The Genetics of BRAF Fusions
The BRAF gene is part of a communication network inside cells that regulates their growth, division, and survival. Under normal circumstances, the BRAF protein is activated only when it receives specific signals, ensuring that cells grow in a controlled manner. A gene fusion event disrupts this regulation when breaks in the DNA of two different genes occur, and the cell’s repair machinery mistakenly joins the wrong pieces.
In a BRAF fusion, the segment of the BRAF gene containing its active kinase domain is preserved and fused to the front part of another gene. There are many different genes that can act as the “partner” in a BRAF fusion, with over 82 different partners identified across various cancers. This partner gene replaces the normal regulatory portion of the BRAF gene, known as the auto-inhibitory domain. This domain normally acts as a safety lock, and its loss leads to a protein that is constantly active.
This structural change is different from a BRAF point mutation, such as the common V600E mutation. A point mutation is like a single spelling error in the gene’s instructions, while a fusion is like pasting a paragraph from one instruction manual into another. This distinction is important because the resulting abnormal proteins behave differently and may respond to different types of drugs.
Role in Cancer Development
The creation of a BRAF fusion protein triggers a cascade of events inside the cell that leads to uncontrolled growth. The fusion protein continuously activates a chain of command known as the mitogen-activated protein kinase (MAPK) signaling pathway. This pathway is a communication system that translates external signals into instructions for the cell to grow and divide. Normally, this pathway is tightly controlled, like a car’s accelerator.
The abnormal BRAF fusion protein essentially jams the accelerator pedal to the floor. It constantly signals to the next protein in the chain, MEK, which in turn signals to another protein, ERK. This relentless activation of the MAPK pathway sends a continuous message to the cell’s nucleus, instructing it to proliferate without stopping.
This unchecked proliferation leads to the formation of a tumor. The cancer cells become dependent on the constant signaling from the BRAF fusion, a phenomenon called “oncogene addiction.” This dependency makes the pathway an attractive target for therapy.
Associated Cancer Types and Diagnosis
BRAF fusions are found in a variety of solid tumors but are generally rare, occurring in approximately 0.3% of all cancers. They are more frequently identified in specific cancer types, including certain brain tumors like pilocytic astrocytomas, where they can be found in over 50% of cases. They are also detected in some thyroid cancers, lung adenocarcinomas, and pancreatic acinar cell carcinomas.
While BRAF point mutations are more common in melanomas, BRAF fusions can also occur in this cancer type. The frequency of these fusions varies; for example, they are seen in about 3% of melanomas and less than 1% of colorectal cancers.
Diagnosing a BRAF fusion requires advanced molecular testing of a tumor sample obtained through a biopsy or surgery. The most common method is Next-Generation Sequencing (NGS), which sequences large portions of the tumor’s DNA or RNA. This allows pathologists to identify the precise point where the BRAF gene has broken and fused with another gene. RNA-based NGS is often preferred for detecting fusions because it directly analyzes the expressed gene products.
Another technique, Fluorescence In Situ Hybridization (FISH), can also be used. This method uses fluorescent probes that bind to specific parts of the BRAF gene. If the gene has been rearranged, the fluorescent signals will appear in an abnormal pattern, indicating a fusion has occurred.
Targeted Treatment Approaches
The discovery of a BRAF fusion in a tumor opens the door to targeted therapy, using drugs designed to interfere with specific molecules involved in cancer growth. Unlike traditional chemotherapy, targeted therapies can be more precise.
The drugs used to treat the common BRAF V600E point mutation, known as BRAF inhibitors, are often ineffective against BRAF fusions. In some cases, these drugs can paradoxically activate the MAPK pathway in cells with BRAF fusions, making the cancer grow faster. This is because fusions cause BRAF proteins to pair up in a way that is resistant to these specific inhibitors.
Instead, the most common treatment for BRAF fusion-positive cancers involves drugs called MEK inhibitors, such as trametinib and selumetinib. These drugs work by blocking MEK, the protein directly downstream of BRAF in the signaling cascade. By inhibiting MEK, the “always on” signal sent by the BRAF fusion protein is intercepted, shutting down the command to grow and divide.
Clinical trials have shown that MEK inhibitors can be effective in shrinking tumors in patients with BRAF fusion-positive cancers, including pediatric low-grade gliomas. For example, selumetinib is a recognized treatment for patients with pilocytic astrocytoma harboring a BRAF fusion. Research is ongoing to explore new strategies, including next-generation RAF inhibitors and combination therapies to overcome potential drug resistance.