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MicroRNA profile in gastrointestinal stromal tumors (GISTs) and correlation with KIT/PDGFRA kinase genotype.

10056 Background: Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic mutations of KIT and PDGFRA receptors. However about 10%-15% of adult GISTs do not harbor any KIT or PDGFRA gene mutation and are defined as wild-type (WT). Studies reported that gene expression profile and genome are strongly different between WT and mutated cases. On the contrary, up to now, really few data are available on microRNAs. We studied the miRNA profiles in GISTs correlated with kinase genotype.


METHODS
We analyzed the miRNA profile of 13 GIST tumor samples, of which 9 carry either KIT or PDGFRA mutations, and 4 do not carry any KIT and PDGFRA mutations. Total RNA was labeled, hybridized to Agilent microRNA microarrays; differential microRNAs were selected by a two-fold change cutoff and Benjamini and Hochberg-corrected unpaired t test. Gene targets of differentially expressed miRNAs were selected if supported by at least five Prediction Algorithms out of six (miRDb, PicTar, Elmmo, MiRanda, PITA, TargetScan).


RESULTS
The miRNA profile is different in WT and mutated GIST samples, with 56 microRNAs differentially expressed (0.05 cutoff p-value). By correlation with gene expression profiling data, we identified the miRNA target genes differentially express between WT and mutated tumors. hsa-let-7b and hsa-let-7c microRNAs are the most significantly differentially expressed miRNAs, resulting less expressed in WT samples and able to target IGF1R receptor. We reported that WT-GISTs overexpress IGF-1R, in spite of Copy-Number-Analysis by high-resolution mapping arrays demonstrated no IGF-1R amplification. These data suggest that overexpression of IGF1R in WT-GISTs could be associated to the downregulation of microRNAs targeting these gene. Validation studies on the significance of the identified miRNAs are ongoing.


CONCLUSIONS
WT-GISTs have a different miRNA profile compared with mutated patients. hsa-let-7b and hsa-let-7c, targeting IGF1R, are the most significantly differentially expressed. microRNA expression difference between WT and mutated GISTs needs to be more investigated in order to understand the biological role on the pathogenesis, clinical behavior and treatment responsiveness.