In total, ~85% of GIST patients harbour activating mutations in one of the genes, c-KIT or PDGFRA, while 10-15% of all GIST patients have no mutations in these two genes (KIT/PDGFRA wild-type GIST). Wild-type GISTs could have alterations in genes of the succinate dehydrogenase (SDH) complex, or rarely in KRAS, NRAS or BRAF genes. The clinical benefit of tyrosine kinase inhibitors (TKIs), such as imatinib, depends on the GIST genotype, therefore molecular characterization of GIST has a crucial role in overall management of these patients.
This doctoral study was performed at the Department of molecular diagnostic, Institute of oncology Ljubljana, to molecularly characterize primary tumour samples of patients with metastatic GISTs from the Slovenian Cancer Registry (National Cancer Registry) treated with tyrosine kinase inhibitors (TKIs) between January 2002 and December 2011 at the Institute of Oncology Ljubljana. Direct Sanger sequencing was performed in tumour samples of all patients included in our study to determine mutation spectrum of c-KIT gene (exons 9, 11, 13 and 17) and PDGFRA gene (exons 12, 14 and 18). Moreover, all KIT/PDGFRA wild-type GISTs were tested for the presence of mutations in hot spot regions of KRAS, NRAS, BRAF, PIK3CA and AKT1 genes with quantitative PCR and their expression of SDH complex was assessed by immunohistochemistry. Additionally, we wanted to find out if the location and type of detected mutations have a significant impact on the clinical outcome (progression free and overall survival) of our patients treated with imatinib.
Our study concluded that mutation frequencies of c-KIT and PDGFRA genes observed in Slovenian patients are comparable with published series. In our study 49 different mutations were detected in c-KIT and PDGFRA genes. In c-KIT, 8 novel variants that have never been described in the literature before were identified. Moreover, one patient with double mutant GIST, who had two different mutations in PDGFRA exon 14 was identified, which is reported to be very rare. In KIT/PDGFRA wild-type GIST no mutations were found in KRAS, NRAS, BRAF, PIK3CA and AKT1, where SDH-deficiency was found in two patients. When analysing how the location and type of detected mutations effect patients’ clinical outcome, our study concluded that location of the mutation in c-KIT exon 11 is associated with a favourable clinical outcome of the Slovene GIST patients, while the type of detected mutation is not significantly important for their clinical outcome.
Our study has confirmed that molecular characterization of GISTs is of great diagnostic value for patients with GIST and their appropriate management and treatment with TKIs.
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