Whole-exome sequencing analysis of mutation characteristics in recurrent or metastatic gastrointestinal stromal tumors

Abstract Purpose: Surgical resection for the metastasis and recurrence of gastrointestinal stromal tumors (GISTs) is controversial. Therefore, it is increasingly important to identify clinical factors related to survival and explore the driver genes and mutations in GIST. Patients and Methods: GIST patients who received two surgeries for primary and recurrent and/or metastatic tumors between January 2003 and December 2018 were reviewed. Paired PT (primary tumor), RMT (recurrent and/or metastatic tumor), and normal DNA were whole-exome sequenced to generate comparable data in eight GIST cases. Results: We identified 39 eligible patients with a median overall survival time of 56.7 months (IQR: 9.6-190.3 months). Regular TKI (Imatinib) treatment after primary tumor resection was associated with better OS, while presence of liver metastasis was prognostic for worse OS in GIST patients who received re-surgery due to recurrent and/or metastatic tumors. Compared with normal tissue, mutation of the MUC family in eight PTs and seven RMTs among the eight patients was detected. In the irregular (TKI) group, correlations and differences were noted in KIT mutations between the PT and RMT, while its influence was lower in the other cases. We also found that the mutation signature and subclone indicated the spatial and temporal heterogeneity of the tumor. Conclusions: MUC mutations may be a potential predictor of recurrent and/or metastatic GIST. Treatment with TKI influenced KIT mutations in RMT of GIST patients. Due to the heterogeneity in the PT and RMT, the direction of tumor evolution and progression were not stable and regular.