Mutation Types

Learn about various mutation types. There are several types of gene mutations that can lead to Gastrointestinal Stromal Tumors. These include KIT mutations, PDGFRA mutations and BRAF and SDH mutations. As each of these involves different genes, the course of the disease and the treatments can vary. That is why gene mutation screening is so important for individuals who have been diagnosed with GIST.

The type and location of these mutations has proven to be a strong predictor of how a patient will respond to treatment with targeted drugs such as Gleevec and Sutent.

About 75% of GISTs have a mutation in the gene encoding KIT tyrosine kinase, while about 5% to 8% have a mutation in the related kinase PDGFRA. About 15% do not have identifiable gene mutations, and include those categorized as “wild-type” GIST.

Testing for mutations in the KIT and PDGFRA genes is available through the Molecular Diagnostics Laboratory of Oregon Health & Science University and in several other labs around the country. For a list of testing centers, see below. For GIST patients with prior surgery the test requires a tissue sample from the hospital where the surgery was performed. It is then sent to one of the labs. In some cases where there was no surgery, a biopsy sample may still have adequate tissue to perform the test.

Testing is typically performed in several stages. KIT exons 9 and 11 are screened first, as about 75% of GISTs will have a mutation in one of these two exons. An exon is the part of the gene containing coding information. KIT exons 13 and 17 and PDGFRA exons 12 and 18 are screened next. If no mutations are found in these exons, the tumor is presumed to be wild-type.

Testing for SDH and BRAF mutations are not yet part of a standard mutational test. BRAF testing is available through both Oregon Health Sciences University and Memorial Sloan Kettering Cancer Center. SDH testing is available from the National Institutes of Health.

Treatment decisions may be influenced by the type of gene mutation. Patients with GISTs with an exon 11 mutation have better responses to the drug Gleevec and better overall survival than those with exon 9 mutations. GISTs with exon 9 mutations have a lower response rate to Gleevec therapy when compared to exon 11 mutations and they seem to require a higher dosage of Gleevec. With the appropriate higher dose, the response of exon 9 patients tends to approach that of exon 11 patients. Exon 9 patients also seem to respond fairly well to the second-line drug Sutent. As many as two-thirds of PDGFRA mutations do not respond to these drugs. For wild-type GIST, Sutent may provide more benefit and there are anecdotal reports of benefit with Tasigna.

Despite a cancer task force recommendation that metastatic and high-risk GIST patients do mutational screening, only about 8% of GIST patients in the United States are tested. The Life Raft Group is working to encourage mutational screening for GIST patients.

Other Mutational Testing Sites: