On the surface of many cells in the body is a protein called Platelet-Derived Growth Factor Receptor Alpha, or PDGFRA. This protein has a role in managing cell activities, including growth and division. It receives signals that are important for the development of many types of cells. When doctors refer to the PDGFRA marker, they are talking about this protein acting as a biological signpost that can provide specific information about a patient’s health.
The Role of PDGFRA in the Body
The PDGFRA protein is part of a family of proteins called receptor tyrosine kinases, which transmit signals from the outside of a cell to the inside. Normally, PDGFRA functions like a controlled switch. It waits for a specific signal, a molecule called platelet-derived growth factor (PDGF), to bind to it. This binding activates the PDGFRA protein, triggering internal signals that tell the cell when to grow, divide, or survive.
These signaling pathways are tightly regulated. However, genetic mutations in the PDGFRA gene can disrupt this control, causing the protein to become permanently activated. This means the protein continuously sends growth signals into the cell, even without the proper external PDGF signal. This constant activation leads to uncontrolled cell proliferation, a primary driver of tumor formation.
Cancers Associated with PDGFRA Alterations
Alterations in the PDGFRA gene are linked with gastrointestinal stromal tumors (GISTs). These sarcomas can arise anywhere along the gastrointestinal tract but are most often found in the stomach or small intestine. While most GISTs are driven by KIT gene mutations, about 5-10% are caused by PDGFRA mutations. In GISTs that lack KIT mutations, this frequency can be as high as 30% to 40%.
Beyond GISTs, PDGFRA alterations are implicated in other cancers. Certain brain tumors, like glioblastoma, can have amplifications of the PDGFRA gene, meaning there are too many copies of the gene. Some rare forms of leukemia are also driven by PDGFRA mutations, such as PDGFRA-associated chronic eosinophilic leukemia. This condition is caused by a gene fusion that drives the overproduction of white blood cells called eosinophils.
Testing for the PDGFRA Marker
To determine if a tumor has a PDGFRA alteration, laboratory tests are performed on a tissue sample from a biopsy. One initial method is immunohistochemistry (IHC), which uses antibodies to stain for the PDGFRA protein on cancer cells. A high amount of staining can suggest the gene is overactive. For a more definitive answer, genetic testing is employed to look for specific mutations.
- Polymerase Chain Reaction (PCR) and Sanger sequencing read the genetic code in specific parts of the gene where mutations are frequently found.
- Next-Generation Sequencing (NGS) analyzes the entire gene or a large panel of cancer-related genes at once.
- Fluorescence In Situ Hybridization (FISH) uses fluorescent probes to detect abnormalities like gene fusions or amplifications.
The results from these tests are important for confirming a diagnosis and guiding treatment strategies.
Implications for Treatment
Identifying a PDGFRA mutation in cancer cells is important because it opens the door for targeted therapy. This approach uses drugs designed to attack cancer cells by interfering with molecules that drive their growth, like the mutated PDGFRA protein, while having fewer effects on healthy cells. The primary class of drugs used for these cancers are known as tyrosine kinase inhibitors (TKIs), which work by blocking the signaling activity of proteins like PDGFRA. Imatinib is effective against GISTs with certain PDGFRA mutations.
However, the specific type of mutation is important. The most common mutation in PDGFRA-driven GISTs, known as D842V, makes the cancer cells resistant to imatinib and other standard TKIs. This understanding led to the development of newer drugs like avapritinib, a TKI designed to be effective against this D842V mutation. Avapritinib has shown positive responses in patients with this mutation, leading to its approval as a first-line treatment for this specific group.