Detecting Mutations in the Gene c-Kit in Certain Types of Tumors

PCR tests are available to detect internal tandem duplication (ITD) mutations in exon 11 and exon 8 of the gene c-Kit in dogs and in exon 8 in cats. Tumors in which mutations in the c-Kit gene have been detected include canine and feline mast cell tumors (MCTs) and canine gastrointestinal stromal tumors (GIST) and have been suspected in canine oral melanomas.

ITD mutations in exon 11 of c-Kit have been detected in about 20 to 30 percent of canine cutaneous MCTs. ITD mutations in exon 8 of c-Kit are less common and have been detected in 2 to 5 percent of canine cutaneous MCTs but have not been shown to be associated with prognosis. Both of these PCR tests are included in our canine mast cell tumor prognostic panel, but can also be ordered as individual tests.

Most cutaneous MCTs in cats are benign and cured by complete surgical excision. Occasionally, more aggressive feline cutaneous, enteric, and visceral MCTs (generally affecting the spleen and/or liver) are seen. For these more aggressive forms, we also offer PCR to detect mutations in exon 8 of c-Kit. Mutations have been detected more commonly in non-cutaneous, aggressive tumors.

In addition, it is important to perform immunohistochemical (IHC) labeling for the protein encoded by c-Kit, a tyrosine kinase receptor called KIT, in all canine nonangiogenic nonlymphogenic gastrointestinal sarcomas. Those tumors that are positive for KIT are called GISTs. A GIST is a particularly aggressive type of gastrointestinal sarcoma. Many canine GISTs also have an activated mutation in exon 11 of c-Kit.

Other Ways to Evaluate c-Kit

As mentioned above, we can also perform IHC for KIT. Aberrant expression of this protein can be identified in cells based on the pattern of immunolabeling. For canine MCTs, there are three types of KIT patterns (1, 2, and 3). In feline MCTs KIT expression has been evaluated in some studies, but is of less prognostic value than in canine MCTs. Any positive immunolabeling for KIT in a nonangiogenic nonlymphogenic gastrointestinal sarcoma is consistent with a GIST.

Why It’s Important to Know Whether a Tumor Has a c-Kit Mutation or Abnormal KIT Expression

Detection of c-Kit mutations in exon 11 predicts a high rate of metastasis and mortality in canine MCTs, but both MCTs and GISTs with such mutations have been shown to respond well to tyrosine kinase-inhibiting (TKI) therapies, e.g. toceranib phosphate (Palladia) and masitinib mesylate (Kinavet-CA). While no prognostic value has been established for detecting mutations in exon 8 of c-Kit in canine and feline MCTs, tumors with a mutation in exon 8 of c-Kit are also expected to respond to TKIs. In addition, aberrant KIT expression patterns (patterns 2 and 3) in canine MCTs have been linked with decreased survival as has cytoplasmic localization of KIT in feline MCTs.