Journal Article

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

Nagashima, Takeshi, Mochizuki, Tohru, Ohshima, Keiichi, Sugino, Takashi, Tsubosa, Yasuhiro, Yamaguchi, Ken, Shiomi, Akio, Terashima, Masanori, Urakami, Kenichi, Uesaka, Katsuhiko, Watanabe, Yuko, Fujiya, Keiichi, Akiyama, Yasuto, Serizawa, Masakuni, Naruoka, Akane, Moromizato, Sachi, Shimoda, Yuji, Kusuhara, Masatoshi, Ohnami, Sumiko, Ohnami, Shumpei, Hatakeyama, Keiichi

2019

Overview

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification‐dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high‐risk GIST) and less malignant GIST (low‐ and very low‐risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K‐related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST. Signaling pathways involved in 65 GIST samples were investigated. Pathways were curated by genetic alterations, including oncogenic mutations and amplification‐dependent expression enhancement for oncogenes, and loss of heterozygosity and expression reduction for tumor suppressor genes. Malignant GIST with metastasis and high‐risk showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K and the cell cycle.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 1-Phosphatidylinositol 3-kinase / AKT1 protein / Cancer / Cell adhesion & migration / Cell cycle / Chromosomes / Copy number / Cyclin-dependent kinase 4 / Deoxyribonucleic acid / Disease Progression / DNA / driver gene / Esophagus / Gastrointestinal Neoplasms - genetics / Gastrointestinal Stromal Tumors - genetics / Gene expression / Genes, Tumor Suppressor / Genomes / Genomics / Heterozygosity / Humans / integrative molecular profiling / Kinases / Loss of Heterozygosity / malignant GIST / Metastases / Metastasis / Mutation / Oncogenes / Original / Phosphatidylinositol 3-Kinases - physiology / PI3K / PTEN protein / Receptor, Platelet-Derived Growth Factor alpha - genetics / Rectum / Signal transduction / Signal Transduction - physiology / signaling pathway / Small intestine / Snail protein / Substance abuse treatment / Tumor suppressor genes / Tumors