Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Imatinib: gastrointestinal stromal tumor. Treatment with imatinib (Gastrointestinal stromal tumor -GIST-) - KIT and PDGFRA genes

Gastrointestinal stromal tumors (GIST) originate from the interstitial cells of Cajal, regulators of digestive tract motility. Are the most common mesenchymal tumors of the gastrointestinal tract, representing 20 to 30% of all soft tissue sarcomas. The tumors are located in the stomach (60-70%), small intestine (25-30%), colorectal (5%) and esophagus (2%). Those affected are usually individuals aged 40-70 years. Initial clinical symptoms are variable, but manifest among other symptoms, abdominal pain, fever, gastrointestinal bleeding and intestinal obstructions. In addition, people with a family history of GIST often develop multiple tumors and other signs or symptoms, including hyperplasia of other cells in the gastrointestinal tract and skin dark areas in various parts of the body. Some people affected develop urticaria pigmentosa, also known as cutaneous mastocytosis.

This may be due to alterations in many genes. In most cases, affected individuals have changes in the KIT (80% of cases) gene, and the PDGFRA gene (8-15% of cases), both located on the long arm of chromosome 4 (4q12 ). The interstitial cells of Cajal express on their membrane the KIT receptor for stem cell factor (SCF: Stem Cell Factor). KIT receptor interaction with its ligand SCF causes activation and release of an intracellular signal that alters gene transcription, cell proliferation and apoptosis. This occurs under normal conditions, but in most individuals with GIST (80%) attend a mutation in the KIT gene that cause the constitutive activation independent of ligand binding, which promotes the survival and continued cell proliferation and inhibits apoptosis. A subset of individuals affected by GIST (8-15%) are carriers of other activating mutations in the PDGFRA gene encoding another receptor tyrosine kinase, receptor alpha platelet derived growth factor. PDGFRA gene mutations related to GIST create a protein that no longer requires the binding of the protein growth factor , platelet derived to be activated. Consequently, PDGFRA protein and signaling pathways are active constitutively, which increases the proliferation and cell survival, leading to tumor formation.

Imatinib (GleevecĀ®) is a small molecule that acts as a selective inhibitor of some tyrosine kinase domains (ABL-BCR, KIT and PDGFR), so is employed as preferential treatment in cases of malignant GIST and can also be used in some mastocytosis and cases of chronic myeloid leukemia (CML) - see mastocytosis. Imatinib therapy and chronic myeloid leukemia. Imatinib- treatment.

Genetic alterations of the KIT gene and PDGFRA gene differ in form and the protein domains involved. These differences result in differences in tumor aggressiveness and the likelihood of clinical response to imatinib. However, there are also differences in response to treatment with imatinib among individuals with mutations in the KIT gene in different exons located. In general, patients with mutations in the KIT gene respond better to treatment than those with localized anomalies in the PDGFRA gene. In fact, the latter have eight times the risk of disease progression than the former. However, the presence of the mutation D816V in exon 17 of the KIT gene, as in many cases of mastocytosis - see mastocytosis. Imatinib- treatment confers resistance to imatinib. It has also been determined that those affected by GIST with mutations in exon 11 of the KIT gene respond significantly better to treatment with imatinib than those patients whose alterations are located in exon 9. In individuals with GIST due to mutations in the PDGFRA gene also differences in the response to imatinib, depending on whether they are located in exon 12 or 18, the first best responding. Cases generated by the majority mutation in PDGFRA (50-60%), the D842V not respond to treatment with imatinib.

Thus, from a genetic analysis based on sequencing of exons which can localizase associated mutations GIST, relatively simple and highly reliable, you can predict the type of response to imatinib develop each patient, allowing an adaptation individualized treatment.

In a small number of individuals with gastrointestinal stromal tumor (GIST), have been identified variations in BRAF (7q34), SDHA (5q15), SDHB (1q36.1-p35), SDHC (1q23.3) and SDHD genes ( 11q23). The loss of activity of the encoded genes from these enzymes results in tumor formation.

Most cases of GIST are not inherited, but are associated with somatic mutations that occur only in tumor cells during a person 's life. In some cases of familial GIST, including those associated with mutations in KIT and PDGFRA genes, mutations are inherited as an autosomal dominant, which means that a copy of the altered in every cell gene is sufficient to increase the probability of developing tumors. When familial GIST is associated with mutations in other genes, you may have an autosomal recessive inheritance pattern, which means that both copies of the gene in every cell must have mutations to increase the probability of developing tumors.

Tests in IVAMI: in IVAMI perform detection of mutations associated with gastrointestinal stromal tumor (GIST), by complete PCR amplification of the exons of the KIT and PDGFRA genes, respectively, and subsequent sequencing. It is recommended to begin the study by exons 9,11, 13 and 17 of the KIT gene and exons 12 and 18 of the PDGFRA gene where mutations identified thus far are located.

Samples recommended: when most caused by somatic mutations, tissue from biopsy is required even if they are embedded in paraffin.