The KIT gene provides instructions for making a protein from a family of signaling proteins known as receptor tyrosine kinases. A mutation in a specific part of this gene, exon 11, is a significant biomarker for certain cancers, particularly Gastrointestinal Stromal Tumors (GISTs). The presence of a KIT exon 11 mutation serves as an indicator for diagnosis and fundamentally alters the selection of treatment strategies for these cancers.
The Biological Function of the KIT Gene
The KIT proto-oncogene directs the production of the KIT protein, a receptor on the surface of various cells. In a healthy state, this receptor waits for a protein called stem cell factor to bind to it. This binding activates the receptor, triggering internal signals that regulate cellular growth, survival, and differentiation. The KIT protein is involved in the development and maintenance of hematopoietic stem cells, mast cells, and the interstitial cells of Cajal, which help control digestive tract contractions.
An exon is a segment of a gene’s DNA that contains instructions for building part of the final protein. The KIT gene has multiple exons, and exon 11 codes for a region of the protein near the cell’s internal membrane called the juxtamembrane domain. This domain acts as an internal off-switch, keeping the receptor inactive until a signal arrives.
A mutation in exon 11 disrupts this regulatory function by damaging the off-switch. The result is a KIT protein that is permanently stuck in the “on” position, continuously sending growth signals into the cell without an external trigger. This uncontrolled signaling, like a car’s gas pedal stuck to the floor, drives constant cell division and proliferation, leading to tumor formation.
Associated Medical Conditions
The most prominent medical condition driven by a KIT exon 11 mutation is the Gastrointestinal Stromal Tumor (GIST). GISTs are a type of sarcoma, a cancer of connective tissues, that can develop anywhere along the gastrointestinal tract. The most common locations for these tumors are the stomach and the small intestine.
The link between GISTs and this genetic alteration is strong. Approximately 80% of all GISTs have a mutation in the KIT gene, and of those, over 70% occur within exon 11. This high frequency makes the KIT exon 11 mutation a defining characteristic of most GISTs, distinguishing them from other sarcomas.
While GISTs are the primary cancer associated with this mutation, it is implicated in other rare conditions. Systemic mastocytosis, a disorder of overproduced mast cells, is linked to KIT mutations, although often in different exons. Certain rare melanomas, such as those on the palms, soles, or mucosal surfaces, have also been found to harbor KIT mutations, including in exon 11.
Diagnostic Process and Genetic Testing
The diagnostic process may begin when a person experiences non-specific symptoms. These can include abdominal pain, a feeling of fullness, bleeding in the digestive tract leading to anemia, or a palpable mass.
Initial diagnostic procedures involve imaging studies to visualize the gastrointestinal tract. A computed tomography (CT) scan can identify the location, size, and extent of a suspected tumor. Endoscopy allows for direct visualization of the digestive system’s inner lining to help pinpoint a mass or source of bleeding.
A definitive diagnosis requires a tissue sample obtained through a biopsy. A pathologist examines the tissue to confirm the cell type. For suspected GISTs, the pathologist performs immunohistochemistry to check for the overexpression of the KIT protein, also known as CD117.
The final diagnostic step is molecular testing of the tumor tissue. This genetic analysis identifies the specific error driving the cancer by sequencing the DNA from tumor cells. Determining if a mutation exists within the KIT gene, and specifically in exon 11, confirms the diagnosis and directly informs treatment decisions.
Targeted Therapy and Treatment Response
Identifying a KIT exon 11 mutation is important for treatment because it makes cancer cells susceptible to targeted therapies. Unlike chemotherapy, these drugs interfere with specific molecular targets. For GISTs with this mutation, the target is the overactive KIT protein, and the primary drugs used are tyrosine kinase inhibitors (TKIs) that block its signaling activity.
The first-line treatment for GISTs with a KIT exon 11 mutation is a TKI called imatinib. This drug is effective because it fits into the KIT protein where the energy-carrying molecule ATP would bind, preventing continuous growth signals. The response rate to imatinib for patients with an exon 11 mutation is around 80%, as the cancer is highly dependent on the KIT pathway.
The specific type of KIT mutation influences treatment response. Patients with mutations in KIT exon 9 may also respond to imatinib but require a higher dose. If a tumor develops resistance to imatinib, second-line therapies like sunitinib and third-line options like regorafenib are available. These are also TKIs that work in slightly different ways to overcome resistance.
Prognosis and Long-Term Monitoring
The prognosis for patients with GISTs driven by a KIT exon 11 mutation has improved with targeted therapies. The outlook is more favorable compared to those with other KIT mutations, like exon 9, or tumors with no KIT mutation (wild-type). This is due to the high sensitivity of exon 11-mutated tumors to the first-line treatment imatinib.
The specific type of exon 11 mutation can also influence prognosis. For example, deletions involving codons 557 and 558 are associated with more aggressive tumor behavior and a higher risk of recurrence after surgery. Despite this, these tumors still show a good response to imatinib therapy.
Due to the risk of recurrence or drug resistance, long-term monitoring is part of the care plan. Patients have regular follow-up appointments and periodic imaging, such as CT scans, to watch for signs of tumor return or growth. This monitoring allows for timely adjustments to the treatment strategy, like switching to a different TKI if resistance emerges.