Translational aspects of Gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, driven by mutations in KIT and PDGFRA in the majority of cases. This thesis explores several translational approaches to improve the diagnosis, treatment, and follow-up of GIST patients. Study I demonstrated excellent long-term outcomes for non-high-risk GIST, with low recurrence rates, in a multicenter cohort. The need for intensive follow-up in this group is therefore questioned. Study II explored ctDNA detection in surgically resected GIST, revealing its potential as a prognostic tool, particularly in high-risk and metastatic cases. Studies III and IV evaluated GRPR and SDHB/MGMT expression in a large cohort of GIST tumors. GRPR was highly expressed in most GISTs although neoadjuvant imatinib treatment was associated with a significantly reduced GRPR expression. Radiotherapy targeting GRPR in GIST might therefore be feasible. SDHB-deficient tumors showed poor outcomes, particularly in combination with MGMT-negativity which indicates the potential for treatment with temozolomide. The findings of this thesis suggest a need to refine follow-up protocols for non-high-risk GIST and support further investigation into ctDNA as a biomarker. Alternative treatments are needed for TKI-resistant GIST where targeted radiotherapy and temozolomide may be options for selected patients.