Sachin Sarcoma Society
Mutation Testing GIST

Mutation Testing GIST

What is mutation?

A mutation is a change in genes that creates an abnormal protein. An abnormal protein provides different information than a normal protein. This can cause cells to multiply uncontrollably and become cancerous.

What is mutational testing?

Mutational testing is a type of biomarker testing that is based on DNA sequencing of genes. Different types of mutations can cause different types of cancer. The information gathered can help to guide diagnosis, determine prognosis, and predict the course of your disease. 

Mutations in GIST

In GIST, the most common genes with mutations known or believed to be the driver mutations in GIST are:

KIT  –  ~75-80%

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. Exon 11 mutations are found in about 60-65% 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. They are found in about 10-12% of cases. As a result, a higher dose of Gleevec is generally recommended for patients with advanced/metastatic disease. They also seem to respond fairly well to Sutent.

Exon 13 (3%) and exon 17 (1%) mutations are rare in GIST. Primary exon 13  (typically K642E) mutations generally respond well to imatinib, however primary exon 17 mutations are more often non-responsive to imatinib.

  • PDGFRA – ~8-10%

Some GIST tumor cells do not contain c-kit mutations. In about 5-8% of all GIST cases, a closely related gene, PDGFRA, is mutated. About 1/3 of the PDGFRA mutations may still respond to Gleevec and/or Sutent/Stivarga, but up to 2/3 of PDGFRA mutations do not respond to these drugs.

KIT/PDGFRA WT – ~8-10%

Note: This GIST type has been commonly known as “wildtype GIST”, but is recently recognized as “No Other Specified” or NOS.

GIST tumors that do not have a mutation in KIT or PDGFRA have, in the past, been called “wildtype” GIST. Wildtype means that the gene in question is normal, so a “wildtype GIST” doesn’t really make sense.  It was originally used to indicate that the KIT gene was normal and starting in 2003 (when PDGFRA mutations were discovered), the term wildtype GIST meant that a patient was tested for both KIT and PDGFRA mutations and none were found, thus, KIT and PDGFRA were “wildtype” or normal. This is often abbreviated as KIT/PDGFRA WT (wildtype).

In most cases, if mutational testing is done, it stops after testing the KIT and PDGFRA genes, so if there is no mutation found in those two genes, the patient does not actually know their mutation. This is incomplete testing since as of 2018, we actually know quite a bit about the mutations these patients are likely to have. They include:

  • NF1
  • BRAF
  • NTRK fusion mutations
  • FGFR1
  • And several other genes

Role of mutation testing in GIST

  • The management of GISTs has evolved rapidly over the past two decades, driven by an ever-growing understanding of the disease’s molecular diversity.
  • It helps in the discussion of treatment options in both the adjuvant and metastatic settings and is influenced by the information obtained by sequencing of the KIT and PDGFRα genes. As we look to the future, clinical trial development will become more molecularly focused, specifically looking for targets in each subset of the GIST population.
  • Our understanding of which therapies are most efficacious with each mutation has also established GIST as a model for targeted therapies in solid tumors. Clear guidelines have been developed regarding staging, prognosis, and treatment
  •  A deeper understanding of the molecular pathogenesis and driving role of the proto-oncogenes KIT and PDGRFα has transformed the treatment of both localized and metastatic disease.