Wildtype GIST is found in approximately 15% of all GIST cases. In this type of GIST, the common mutations in KIT and PDGFRA gene are not found. The test performed is called genotyping and involves looking at the DNA sequence from paraffin embedded GIST tumor samples. The test looks for changes such as deletions, insertions, and duplications in the normal sequence of the genes.
At the current time, “wildtype” is more defined by what it isn’t than what it is. Rare mutations, such as SDH, BRAF, and NF1, may or may not be considered wildtype depending on who is defining it. However one thing that most doctors/researchers will agree on is in cases where the mutation is unknown the mutation is considered to be wildtype. It is possible that the definition for wildtype GIST may change in the future with increased understanding of rare mutations. Mutational testing is critical to identify the specific subtype of wildtype GIST, as optimal treatments may vary by subtype.
What does wildtype mean?
In genetics, wildtype is the term used for the typical form of a gene, or characteristic as it was first observed in nature (in the wild). When someone refers to “wildtype KIT”, it means that the KIT gene is “normal”; it has no detectable mutation. Since it is somewhat clumsy to say that a GIST patient has wildtype KIT and wildtype PDGFRA, we often shorten this to say a person has wildtype GIST. It means that they don’t have a mutation in either of the two genes (KIT and PDGFRA) that typically play the dominant role in GIST.
Carney-Stratakis Syndrome, a rare type of familial GIST, is a special case that needs to be noted. Although these patients have wildtype KIT and wildtype PDGFRA, they have a mutation in one of the succinate dehydrogenase genes (SDH). At the present time, these patients are still frequently grouped with others as wildtype GIST. Some patients with either Carney’s Triad or Pediatric-Like GIST also appear to have mutations in one of the SDH subunits.
What about SDH-deficient GIST?
Often mentioned alongside wildtype, SDH-deficient GIST occurs when a patient has a mutation in the succinate dehydrogenase genes (SDH), which affects tumor suppression. Unlike other forms of GIST that don’t discriminate, SDH-deficient GIST tends to disproportionately affect females and young people. Our bodies use these tumor suppressor genes (the SDH) to fight off cancer. This is a problem if cancer develops because the SDH gene is not available to fight the disease. The only way to know if you have the SDH-deficiency is to be tested. It is important to identify your type GIST so that you don’t spend time and health on a drug treatment to which your mutation may not respond. Patients who are SDH-deficient should be tested for familial (inherited) because the SDH-deficient patient is more likely to be pass on the mutation.
Watch this video about how Wild-type GIST is Classified from ESMO.org: