Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GISTs), but insufficient for their malignant progression. Here, we explored to identify driver genes and signaling pathways relevant to GIST progression. We investigated gene expression along with genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, for 65 clinical specimens of surgically dissected GISTs, consisting of 6 metastasis and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations include oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OGs), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSGs). We assigned activated OGs and inactivated TSGs to 27 signaling pathways, whose activation was compared between malignant GISTs (metastasis and high-risk GISTs) and less malignant GISTs (low- and very low-risk GISTs). Integrative molecular profiling indicated that higher incidence of genetic alterations of driver genes were detected more in malignant GISTs (96%, 22 of 23) than in less malignant GISTs (73%, 24 of 33). The malignant GIST samples showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, whose expression was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GISTs. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GISTs.
Overall design
The mRNA expression profiles of 65 GIST tumors were determined using Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray.
Less...
More...