Abstract
Oncogenic mutations in gastrointestinal stromal tumors (GISTs) predict prognosis and therapeutic responses to imatinib. In wild-type GISTs, the tumor-initiating events are still unknown, and wild-type GISTs are resistant to imatinib therapy. We performed an association study between copy number alterations (CNAs) identified from array CGH and gene expression analyses results for four wild-type GISTs and an imatinib-resistant PDGFRA D842V mutant GIST, and compared the results to those obtained from 27 GISTs with KIT mutations. All wild-type GISTs had multiple CNAs, and CNAs in 1p and 22q that harbor the SDHB and GSTT1 genes, respectively, correlated well with expression levels of these genes. mRNA expression levels of all SDH gene subunits were significantly lower (P≤0.041), whereas mRNA expression levels of VEGF (P=0.025), IGF1R (P=0.026), and ZNFs (P<0.05) were significantly higher in GISTs with wild-type/PDGFRA D842V mutations than GISTs with KIT mutations. qRT-PCR validation of the GSTT1 results in this cohort and 11 additional malignant GISTs showed a significant increase in the frequency of GSTT1 CN gain and increased mRNA expression of GSTT1 in wild-type/PDGFRA D842V GISTs than KIT-mutant GISTs (P=0.033). Surprisingly, all four malignant GISTs with KIT exon 11 deletion mutations with primary resistance to imatinib had an increased GSTT1 CN and mRNA expression level of GSTT1. Increased mRNA expression of GSTT1 and ZNF could be predictors of a poor response to imatinib. Our integrative approach reveals that for patients with wild-type (or imatinib-resistant) GISTs, attempts to target VEGFRs and IGF1R may be reasonable options.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract with an annual incidence ranging from 11 to 19.6 per million population, which corresponds to between 3,300 and 6,000 new cases per year in the United States [1]
There were no significant differences in the number of copy number alterations (CNAs) between mutation types or among prognostic risk subgroups
The clinicopathologic data of these 32 gastric GISTs and the CNAs detected by Array comparative genomic hybridization (aCGH) are shown in Figure 1 and Table S1
Summary
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract with an annual incidence ranging from 11 to 19.6 per million population, which corresponds to between 3,300 and 6,000 new cases per year in the United States [1]. Oncogenic KIT and PDGFRA mutations in GISTs correlate with tumor phenotype, prognosis, and therapeutic responses to tyrosine kinase inhibitors [4,5]. Kinase mutation status does not fully explain the complex biology of GISTs. approximately 85% of pediatric GISTs and 10-15% of adult GISTs do not harbor mutations of KIT or PDGFRA genes (so called ‘wild-type’ GISTs) [6,7,8]. Wild-type GISTs are less sensitive to imatinib than GISTs harboring mutations in exon 11 of KIT gene. Patients with progressive disease may be preselected for treatment with imatinib or alternative and/or additional therapies based on their KIT/PDGFRA mutational status and predictive gene signatures of drug response [12]
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