Mutational Testing

Exon Mutations Affect Response Rate

The PowerPoint presentation by Dr. Christopher Corless and Dr. Michael Heinrich which was given at the London GIST conference gives an excellent overview of this topic.

KIT Mutational Status Predicts Clinical Response to Glivec in Patients With Metastatic GIST

Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+)

KIT & PDGFRA mutations in GIST: A to Z by Dr. Michael Heinrich

Looking for kinase mutations in GISTs: how, when and why? by Dr. Christopher Corless

KIT exon mutations in GIST

Mutations in the KIT receptor

The information in genes is divided into different sections called exons and introns. Exons contain coding information and introns do not. Mutations in different exons in the gene cause changes in shape in different parts of the KIT receptor. Mutations in the following exons of the c-kit gene are known to occur in GIST.

Exon 11-This is the most commonly mutated exon in GIST. In phase II trials, exon 11 mutations were found in 68% of cases. Mutations in exon 11 generally respond to treatment with Gleevec better than mutations in other exons.

Exon 9-Exon 9 mutations are the second most common mutation. In phase II trials, exon 9 mutations were found in 16% of cases. They are only known to occur when the primary tumor originates in the small bowel and colon. GISTs with exon 9 mutations have a lower response rate to Gleevec therapy when compared to exon 11 mutations.

Exon 13 and exon 17 mutations are rare in GIST.

Some GIST tumor cells do not contain c-kit mutations. This is called "wild-type" c-kit. GIST with wild-type tumors do not respond as well as other types, but since some signaling may still occur through the KIT receptor and since there is about a 35% chance that PDFGR-Alpha mutations may be involved, and since Gleevec is known to inhibit PDGFR-Alpha and KIT, treatment with Gleevec is beneficial in many cases.

Note: The Life Raft Group is posting this information as provided to us by Oregon Health Sciences University (OHSU). This is not an endorsement and other labs or hospitals might provide this service in the future.

KIT & PDGFRA Gene Mutation Screening

Background Data and Interpretation

Testing for mutations in the KIT and PDGFRA genes is available through the Molecular Diagnostics Laboratory of Oregon Health & Science University (OHSU). This testing can provide physicians and their patients information on the likelihood of response to therapy with imatinib mesylate (STI571; Gleevec^TM), as detailed below. Regardless of the test results, however, all patients eligible for treatment should undergo a therapeutic trial with the drug. Even among patients with tumors lacking a detectable KIT or PDGFRA gene mutation, the response to imatinib mesylate is higher than the response to traditional chemotherapy (<5%).

Approximately 80-85% of gastrointestinal stromal tumors (GISTs) have an oncogenic mutation in the gene encoding KIT tyrosine kinase. Another 5-7% of GISTs have a mutation in the gene encoding the related kinase PDGFRA (platelet-derived growth factor receptor alpha). KIT and PDGFRA mutations are mutually exclusive in GISTs. In both genes, the observed mutations result in expression of a mutant form of kinase that is constitutively “turned on” and helps drive the growth of the tumor. Approximately 7-12% of GISTs have no detectable KIT or PDGFRA gene mutation. What supports the growth of this subset of GISTs remains unclear.

Based on an interim analysis of the CSTI-B2222 phase II trial of imatinib mesylate in the treatment of non-operable malignant GI stromal tumor, there is a relationship between the kinase mutation status of a GIST and the likelihood of drug response, as summarized in the table below.

In addition to having a higher rate of response to therapy, patients with GISTs harboring an exon 11 mutation have more durable responses and better overall survival than those with exon 9 mutations or those with no mutation detected in either kinase gene.

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Methods

Testing is performed in two stages. KIT exons 9 and 11 are screened first, as approximately 80% of GISTs will have a mutation in one of these two exons. KIT exons 13 and 17, and PDGFRA exons 12 and 18 are screened in the second stage. If no mutations are found in these exons, the tumor is presumed to be “wildtype”, although there remains a small (less than 1%) possibility that a mutation was missed elsewhere in either gene.

DNA is extracted and purified from paraffin-embedded tumor tissue. The indicated exons of the KIT and PDGFRA genes are amplified by PCR, and the products are screened for mutations by denaturing HPLC (WAVE system, Transgenomic, Inc.). Based on analysis of over 400 GIST samples, the sensitivity and specificity of this combined HPLC plus sequencing approach are >98%.

How to Order the Test

Requests for KIT and PDGFRA mutation screening must originate from a pathologist or treating physician. One paraffin block of the tumor (either biopsy or surgical specimen) or 15 unstained sections of the tumor should be sent to address listed below. A copy of the original pathology report as well as the patient’s insurance information must be included.

KIT/PDGRRA Mutation Screening Service (Heinrich/Corless lab website)

Other Mutational Testing Sites:

MD Anderson

Testing can only be done with patients who go to MD Anderson.
Phone Number: 713-563-9701.

Expert Opinions: KIT & PDGFRA mutations in GIST: A to Z by Michael Heinrich, M.D.
Looking for kinase mutations in GISTs: how, when and why? by Christopher Corless, M.D., PhD.