Mutational profile of cypriot patients with gist: results from a 15-year cohort

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal (GI) tract. These tumors are usually divided into mutant or wild-type based on the presence or absence of activating mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. Downstream signaling pathways activated by gain-of-function mutations are crucial in GIST development and affect the clinical prognosis and treatment decisions. Although the use of tyrosine kinase inhibitors (TKIs), like imatinib, have a major impact on the overall survival of KIT/PDGFRA mutant patients in both adjuvant and metastatic settings, about 10-15% are imatinib-resistant. Since molecular characterization has a pivotal role in the overall management of GISTs, we aimed to analyze a cohort of 105 patients diagnosed with GIST in the Republic of Cyprus, treated at the Bank of Cyprus Oncology Centre between 2008 and 2023. The mutational profile of a total of 74 formalin-fixed paraffin-embedded tumors was analyzed by next-generation sequencing (NGS) or Sanger sequencing. The most common mutation found was in KIT exon 11 accounting for 52,63% followed by PDGFRA exon 18 accounting for 10,53%. No mutations were detected in 22,37% of cases. Interestingly, we found mutations in KRAS, SMO, and RET genes that were not previously described. GISTs with KIT and PDGFRA mutations were predominantly located in the stomach, and showed spindle cell phenotype, while rare mutations were of omentum epithelioid origin with epithelioid features and high risk of malignant potential. Adverse prognostic factors included the high mitotic index and late-stage disease status at diagnosis. Collectively, the scientific progress in understanding the molecular basis of GISTs justifies the importance of knowing the mutations, if any, to aim for a more personalized approach to treating GIST patients.