Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity

Abstract

Purpose: Gastrointestinal stromal tumors (GIST) commonly arise in different regions of the stomach and are driven by various mutations (most often in KIT, PDGFRA, and SDHx). We hypothesized that the anatomic location of gastric GIST is associated with unique genomic profiles and distinct driver mutations. Experimental Design: We compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST. Additionally, we compiled an international cohort (TransAtlantic GIST Collaborative, TAGC) of 236 patients and reviewed sequencing results, cross-sectional imaging, and operative reports. Subgroup analyses were performed for tumors located proximally versus distally. Risk factors for KIT versus non-KIT tumors were identified using multivariate regression analysis. A random forest machine learning model was then developed to determine feature importance. Results: Within the NCDB cohort, non-KIT mutants dominated distal tumor locations (P < 0.03). Proximal GIST were almost exclusively KIT mutant (96%) in the TAGC cohort, whereas 100% of PDGFRA and SDH-mutant GIST occurred in the distal stomach. On multivariate regression analysis, tumor location was associated with KIT versus non-KIT mutations. Using random forest machine learning analysis, stomach location was the most important feature for predicting mutation status. Conclusions: We provide the first evidence that the mutational landscape of gastric GIST is related to tumor location. Proximal gastric GIST are overwhelmingly KIT mutant, irrespective of morphology or age, whereas distal tumors display non-KIT genomic diversity. Anatomic location of gastric GIST may therefore provide immediate guidance for clinical treatment decisions and selective confirmatory genomic testing when resources are limited.

Extensive mutational ctDNA profiles reflect High-grade serous cancer tumors and reveal emerging mutations at recurrence

“…Studies using next generation sequencing on urothelial cancer [ 32 ] and GIST-tumors [ 33 ] show that different anatomical regions often provide varying genetic information in tissue biopsy. This obstacle could be overcome by using a ctDNA plasma sample since tumor-DNA is shed into the bloodstream from all locations [9] .…”

Neoadjuvant versus adjuvant imatinib in primary localized gastrointestinal stromal tumor

“…Our findings were unable to invalidate the association between NAT and DRFS in stomach GIST. The majority of proximal gastric GISTs are KIT-mutant tumors (30), which also require function preservation. NAT has a key role in the therapy of proximal gastric GIST and distal gastric GIST with sensitive mutations.…”

Fourth-line targeted drugs for the long-term treatment of patients with secondary gastrointestinal stromal tumors with multisite mutations: a case report

“…As gene sequencing was not performed in the early stage, according to the standard treatment with the first-line and second-line drugs, following the detection of a clear secondary mutation in the postline gene, the precise diagnosis and treatment model based on the driver gene was performed for the mutation at multiple sites. For targeted GIST therapy, it is necessary to combine line therapy and precise therapy (13), which requires medical care for the entire course of patient management with regular follow-up and tumor evaluation. The effective control of adverse drug reactions and dose management of TKIs can help extend the duration of drug treatment, maximize the benefits of drug treatment, select the appropriate timing of surgical treatment, combine and transform adjuvant therapy with conversion therapy, and prolong the survival of patients (14-21).…”