Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors. Issue 6 (June 2020)

• Record Type: Journal Article
• Authors: Fujiya, Keiichi; Ohshima, Keiichi; Kitagawa, Yuko; Hatakeyama, Keiichi; Nagashima, Takeshi; Aizawa, Daisuke; Sugino, Takeshi; Urakami, Kenichi; Yamaguchi, Ken; Terashima, Masanori
• Is Part Of: European journal of surgical oncology. Volume 46:Issue 6(2020)
• Page Start: 1080
• Page End: 1087
• Publication Date: 2020-06
• Subjects: β-catenin -- FZD -- Gene expression profiling -- Malignant GIST -- Wnt pathway; GIST gastrointestinal stromal tumor -- PDGFRA platelet-derived growth factor receptor α -- GEP gene expression profiling -- Project HOPE Project High-tech Omics-based Patient Evaluation -- NIH National Institutes of Health -- WES whole exome sequencing -- CCP comprehensive cancer panel -- IHC immunohistochemical staining -- PCA principal component analysis -- FZDs frizzleds receptors -- DVL dishevelled; Oncology -- Periodicals; Cancer -- Surgery -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- surgery -- Periodicals; Cancer -- Chirurgie -- Périodiques; Cancérologie -- Périodiques; Oncologie; Chirurgie (geneeskunde); Electronic journals; Electronic journals -- Sciences; Electronic journals -- Medicine; Electronic journals; 616.994059005
• DOI: 10.1016/j.ejso.2020.02.036
• Languages: English
• ISSNs: 0748-7983

Abstract

Abstract: Introduction: Recent reports on gene expression profiling (GEP) show several genes associated with malignant progression of GIST. However, genes associated with malignant transformation have not been clarified. Here, we aimed to reveal distinct genes in aggressive malignant GIST, using comprehensive gene expression analysis. Materials and methods: We investigated GEP obtained by microarrays for 43 gastric GISTs, which mostly harbored KIT and PDGFRA mutations and integrated clinicopathological risk information. RT-PCR and immunohistochemistry were performed for FZD7, a receptor of Wnt ligands. Results: GEP divided 43 gastric GISTs into two clusters. A cluster included seven of eight high-risk GISTs (88%) in modified NIH classification and was defined as high-risk cluster; the other cluster was defined as low-risk cluster. The number of probes with over 3-fold changes between the two clusters was 1, 177, in which probes corresponding to 16 oncogenes were included. Genes involved in the Wnt signaling pathway were the most abundant among the 16 oncogenes. Focusing on 73 Wnt signaling pathway genes of the 21, 578 probes, 12 upregulated and 5 downregulated genes were found in the high-risk cluster. Major cascade genes promoting the Wnt/β-catenin signaling pathway, including WNT11, FZD family, and DVL2, were upregulated in the high-risk cluster. SNAI1, SNAI2, and BIRC5, which are activated by this pathway and increase cell proliferation, were also upregulated. These gene expression alterations were consistent in the positive direction of this pathway. GISTs in high-risk cluster strongly expressed FZD7. Conclusion: Wnt/β-catenin signaling pathway may play an important role in malignant transformation of indolent GIST. Highlights: - Low and high clinical risk clusters were separated by gene expression profiling - The Wnt/β-catenin signaling pathway was activated in aggressive malignant GIST - Malignant GIST strongly expressed FZD7, a receptor of Wnt ligands