Genomic Profile and Clinicopathologic Analyses of Wild-Type Gastrointestinal Stromal Tumors

The driver genes of wild-type gastrointestinal stromal tumors (WT-GISTs), particularly quadruple WT-GIST (qWT-GIST), remain unclear. In this study, we collected 119 WT-GISTs from two cohorts and analyzed their clinicopathological and genomic features, particularly for qWT-GISTs. Next-generation sequencing (NGS) revealed several fusion genes and gene mutations, such as ARID1B, SETD2, and PLCG2, in qWT-GISTs. Further integrated KEGG pathway analysis revealed significantly enriched signaling pathways in qWT-GISTs, including the HIF-1. For qWT-GISTs, large tumors or a high mitotic index prompted a shorter RFS, and a high mitotic index or involvement of the HIF-1 pathway prompted a shorter OS; however, neither RFS nor OS was prolonged by postoperative adjuvant therapy. In addition, compared with SDH-deficient GISTs, qWT-GISTs were less frequently found in the stomach and less frequently presented as high mitotic index; compared with RAS-related GISTs, qWT-GISTs were more frequently found in the stomach. Stratified analyses showed, in patients with low recurrence risk, qWT-GISTs had better RFS than SDH-deficient GISTs. In patients with high recurrence risk or with postoperative adjuvant therapy, qWT-GISTs presented worse OS than SDH-deficient GISTs. In summary, qWT-GISTs exhibited unique clinicopathological characteristics and outcomes compared to SDH-deficient and RAS-related GISTs, suggesting that they should be managed using different treatment and follow-up strategies, especially stratified management. Considering the rarity and heterogeneity of WT-GISTs, a regulatory detection procedure should be established for WT-GISTs, including NGS for qWT-GISTs, to identify the molecular mechanisms and potential therapeutic targets. Implications: WT-GISTs are heterogenous tumors which should be managed using different treatments and follow-up strategies.