KIT Mutations in Melanoma

Melanoma is a type of cancer that develops from melanocytes, the cells that give skin its color. Melanocytes are also found in other parts of the body, including the lining of the mouth, nose, and genital and anal areas, and melanoma can begin in any of these locations. KIT testing is a biomarker test performed on some melanomas to look for a change (mutation) in a gene called KIT. A “biomarker” is a measurable feature of cancer, such as a change in a gene, that provides doctors with information they cannot get from looking at cells under the microscope alone. When a melanoma carries a specific KIT mutation, the cancer may respond to a group of targeted drugs called KIT inhibitors.

This article will help you understand what a KIT result means on a melanoma pathology report, why the test is done, how it is performed, and how the result may guide treatment decisions. KIT mutations are uncommon in melanoma overall, but they are concentrated in particular subtypes, so the test is most useful for certain patients. Finding a KIT mutation does not change what type of cancer you have, and it is not an inherited change passed down in families. It is a change that happened within the tumor itself, and its main importance is that it can open up a specific treatment option.

What is KIT?

KIT is a gene that gives cells instructions to make a protein, also called KIT (or CD117), that sits on the cell surface and helps control when the cell grows and divides. You can think of the KIT protein as an antenna that receives “grow and divide” signals from outside the cell and passes them inward. Normally, this antenna sends its signal only when it receives the right message, and then switches off again.

A mutation in the KIT gene can change the shape of the KIT protein so that it is stuck in the “on” position, sending a constant grow-and-divide signal even when it should not. This drives the uncontrolled growth that defines cancer. The same gene is important in other tumors, most famously a stomach and bowel tumor called gastrointestinal stromal tumor (GIST), where KIT inhibitor drugs were first shown to work. In melanoma, only a minority of tumors carry a KIT mutation, but when one is present, it can be the key to a targeted treatment option.

Why is KIT testing done in melanoma?

KIT testing in melanoma is done because a mutation in the KIT gene can predict whether the cancer is likely to respond to a group of targeted medicines called KIT inhibitors. These drugs are designed to block the overactive KIT protein and switch off the constant grow-and-divide signal that the mutation produces. Because these medicines only help when a responsive KIT mutation is present, the test is used to decide whether they are an option.

KIT mutations are found in fewer than 5 percent of melanomas overall, so KIT testing is not useful for every melanoma. Instead, the mutation is concentrated in particular subtypes of melanoma that are not caused by ordinary sun exposure. These include acral melanoma, which arises on the palms, the soles of the feet, or under the nails; mucosal melanoma, which arises on the moist inner linings of the body, such as the mouth, nose, and genital and anal areas; and melanoma that arises on skin with long-term, chronic sun damage. For this reason, KIT testing is generally performed when a melanoma belongs to one of these subtypes, particularly when the disease has spread and targeted treatment is being considered. It is usually unnecessary for common types of melanoma arising on intermittently sun-exposed skin, because KIT mutations are very rare in those tumors.

How is KIT testing performed in melanoma?

KIT testing in melanoma looks for a mutation in the KIT gene, which can predict response to KIT inhibitor therapy. The test is performed on a sample of the melanoma that has already been removed, so it does not usually require an additional procedure. The same tissue taken at the time of biopsy or surgery, stored as a paraffin block, is used. Two types of tests may be involved.

Gene sequencing (PCR or next-generation sequencing) — This is the main test for KIT in melanoma. It reads the genetic code of the KIT gene directly to find a mutation and, importantly, to identify exactly which mutation is present. Next-generation sequencing reads many genes at once and is often used to check KIT, BRAF, and other relevant genes from the same sample. Knowing the specific mutation matters because only certain KIT mutations respond well to KIT inhibitor drugs.
Immunohistochemistry for the KIT protein (CD117) — This method uses an antibody to stain the KIT protein (CD117) on a thin slice of the tumor on a glass slide. It shows whether the protein is present but does not identify a mutation, and the amount of protein does not reliably predict whether a drug will work. For this reason, a positive protein stain is usually followed by gene sequencing to determine whether a treatable mutation is actually present.

How are KIT results reported in melanoma?

KIT results in melanoma describe whether a mutation was found in the KIT gene, which can predict response to KIT inhibitor therapy. Your report will describe the result in one of the following ways.

KIT mutation detected (positive) — A mutation was found in the KIT gene. The report will usually name the specific mutation, such as L576P or K642E. The exact mutation matters because some KIT mutations respond well to KIT inhibitor drugs while others respond poorly or not at all. The report may also note the part of the gene (the exon) where the mutation is located.
No KIT mutation detected (wild-type or negative) — No mutation was found in the parts of the KIT gene that were tested. The report may use the term “wild-type,” which simply means the normal, unmutated form of the gene. This result indicates that KIT inhibitor drugs are unlikely to be effective, and the treatment team will focus on other options.
KIT amplification — Some reports describe extra copies of the KIT gene rather than a mutation in it. This is called amplification. Amplification is a separate finding from a mutation, and on its own it is a less reliable predictor of response to KIT inhibitor drugs than a specific activating mutation.
CD117 (KIT protein) positive by immunohistochemistry — When the result comes from the antibody-based stain, the report describes whether the tumor cells showed the KIT protein. Because protein staining does not identify a treatable mutation, this result is usually interpreted together with gene sequencing rather than on its own.

What does a KIT result mean for melanoma treatment?

The KIT result in melanoma tells the treatment team whether the cancer carries a KIT mutation that may respond to targeted medicines called KIT inhibitors. This information is most relevant when melanoma has spread to nearby lymph nodes or to distant organs (metastasis), because that is the setting in which these drugs are used. The pathology report does not prescribe treatment; the KIT result is one of several findings the team weighs together when discussing options with the patient.

When a responsive KIT mutation is present, treatment with a KIT inhibitor becomes an option. These drugs are taken as pills and work by blocking the overactive KIT protein. The KIT inhibitor most commonly used in melanoma is imatinib, and related drugs such as nilotinib may also be considered. An important point is that not every KIT mutation responds equally; certain mutations (for example, those in exon 11 or exon 13) tend to respond better than others. This is why the report identifies the specific mutation rather than simply stating that KIT is mutated.

When no KIT mutation is present, KIT inhibitor drugs are unlikely to be effective, and the team will focus on other systemic options. For most melanomas, the two most important treatment pathways are immunotherapy, which helps the immune system attack the cancer, and, for tumors with a BRAF mutation, BRAF-targeted therapy. KIT-mutant melanomas are also still candidates for immunotherapy, and the medical oncology team determines the sequencing of these options based on the full clinical picture. The melanoma’s BRAF status, as well as PD-L1 and tumor mutational burden, are described in separate articles.

Is a KIT mutation inherited?

The KIT mutation found in melanoma is not inherited and is not passed down to children. It is a “somatic” mutation, meaning it developed within the melanoma cells during a person’s lifetime rather than being present in the genes a person is born with. Because the mutation is present only in the tumor and not in the body’s other cells, it does not appear on a test for inherited cancer risk and has no implications for family members. A KIT result on a melanoma pathology report is purely about guiding treatment for the cancer that is already present.

What happens after KIT testing?

Once KIT testing on the melanoma is complete, the result becomes part of the information the treatment team uses to plan care. The KIT result is considered alongside the melanoma subtype, the cancer stage, whether it has spread, the BRAF status, and the patient’s overall health. For a melanoma that has spread and carries a responsive KIT mutation, a KIT inhibitor such as imatinib may be considered. When no mutation is present, attention turns to immunotherapy and, where relevant, BRAF-targeted therapy.

Melanoma care usually involves a multidisciplinary team that may include a medical oncologist, a surgeon, a radiation oncologist, a dermatologist, and a pathologist. The medical oncologist typically leads decisions about systemic therapy, including whether targeted therapy or immunotherapy is the better fit. If a KIT inhibitor is started, patients are monitored for side effects and for signs that the cancer is responding. Over time, some melanomas that initially respond to a KIT inhibitor can develop resistance, meaning the drug stops working as well; when this happens, the team reassesses and considers other options. Because KIT-mutant melanomas often belong to the acral or mucosal subtypes, which can be diagnosed at later stages, close follow-up with imaging and physical examination is an important part of care.

Questions to ask your doctor

Was my melanoma tested for a KIT mutation, and what was the result?
What subtype of melanoma do I have, and does it make a KIT mutation more likely?
If a KIT mutation was found, which specific mutation is it, and is it a type that tends to respond to treatment?
Was my result based on gene sequencing, protein staining, or both?
Does my KIT result mean that a KIT inhibitor such as imatinib is an option for me?
How does my KIT result fit together with my BRAF result and the stage of my melanoma?
If I have a KIT mutation, would you consider a KIT inhibitor, immunotherapy, or both, and in what order?
What are the possible side effects of KIT inhibitor therapy?
If no KIT mutation was found, what treatment options are available to me?
How will we know if the treatment is working, and what happens if the cancer becomes resistant?