Abstract 2170: Microarray analysis reveals distinct gene set profiles between gastric and intestinal gastrointestinal stromal tumors

Abstract

Background: Gastrointestinal stromal tumor (GIST) is known to originate from the interstitial cells of Cajal or its precursors with a gain-of-function mutation of the c-kit or PDGFRA gene. GISTs are most commonly found in the stomach, followed by the small intestine. It is known that patients with intestinal GIST have markedly higher risks for recurrence compared to those with gastric GISTs. According to Miettinen's risk classification, intestinal GISTs are categorized in higher risk group compared with gastric GISTs at the same size and mitotic index. In this study, we sought to address mechanisms underlying the clinically malignant phenotype of intestinal GISTs. Methods: Fresh frozen samples of 6 primary gastric GISTs, 3 primary intestinal GISTs and 6 metastatic liver GISTs were utilized for cDNA microarray analysis. None of the patients had received imatinib therapy before surgery. Gene expression levels were compared between primary gastric and intestinal GISTs using gene set enrichment analysis (GSEA). Protein levels of SLIT2 were analyzed by immunohistochemistry in 25 primary gastric GISTs and 10 intestinal GISTs. Results: Microarray analysis of primary gastric and intestinal GISTs and metastatic liver GISTs classified them into two groups according their gene expressions. One group consisted of primary gastric GISTs without postoperative recurrence and the other consisted of clinically malignant GISTs, intestinal GISTs and metastatic liver GISTs, suggesting that intestinal GISTs potentially show gene expression profile similar to clinically malignant and metastatic GISTs. GSEA revealed that the gene set MITOTIC_CELL_CYCLE was upregulated in intestinal GISTs compared with gastric GISTs, consistent with previous reports that intestinal GISTs show higher mitotic count. The gene set NEURON_DIFFERENTIATION was downgulated in intestinal GISTs compared with gastric GISTs that may help explain mitosis-independent mechanisms underlying the clinically malignant phenotype of intestinal GISTs. In this gene set, we focused on SLIT2, downregulation of which has been reported to be associated with aggressive phenotypes in human cancers. Immunohistochemistry revealed that intestinal GISTs expressed lower SLIT2 protein than gastric GISTs, and that high-risk gastric GISTs and intestinal GISTs express comparable levels of SLIT2 protein which were lower than low-risk gastric GISTs. In SLIT2-high GISTs, tumor size was significantly smaller than in SLIT2-low GISTs, whereas mitotic counts and MIB-1 index were comparable among three groups according to SLIT2 intensity. Conclusions: Gene expression profile of intestinal GISTs was similar to that in metastatic liver GISTs. Expression levels of SLIT2 protein were lower in intestinal GISTs compared with gastric GISTs. Besides higher proliferative activity, downregulation of SLIT2 could be involved in clinically malignant phenotypes of intestinal GISTs. Citation Format: Hirotoshi Kikuchi, Ryuhei Hara, Shinichiro Miyazaki, Yoshihiro Hiramatsu, Kinji Kamiya, Manabu Ohta, Takanori Sakaguchi, Satoshi Baba, Haruhiko Sugimura, Hiroyuki Konno. Microarray analysis reveals distinct gene set profiles between gastric and intestinal gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2170. doi:10.1158/1538-7445.AM2015-2170