Activating mutations in the KIT and PDGFRA genes result in ligand independent activation of their receptor tyrosine kinase function, which may trans mit early oncogenic signals in the majority of GISTs. so Even though the biological consequences of KIT and PDGFRA mutations seem to be similar, our study has revealed hundreds of differentially expressed genes that group the tumours according to the receptor mutation sta tus and receptor gene expression. However, although many of these genes may be involved in receptor specific alterations of GIST intracellular signalling pathways, we identified no discriminative profiles of gene expression associated with clinical or pathological outcomes. Most of the discriminative genes were found to be upregulated in PDGFRA mutated GISTS.

To further clarify if gene signatures that group GISTs according to KITPDGFRA mutation status, as described Inhibitors,Modulators,Libraries previously, may be defined also at the level of intracellular signalling pathways, we analyzed microarray data in the context of functional annotation. Among terms and pathways in the current analysis with the highest overrepresentation in GISTs with mutated andor overexpressed PDGFRA were blood vessel develop ment and angiogenesis. In fact, GISTs are highly vascu larised tumours, and VEGF expression has been postulated to be a KIT genotype independent adverse prognostic indicator for early treatment failure and poor survival of GIST patients on imatinib therapy. We also found that the functional features of genes differ entially expressed between the two groups of GISTs were represented by the G protein coupled receptor protein signalling pathway.

The regulated secre tion of transmitters and hormones, a characteristic event of neuroendocrine cells and tumours, is controlled by G protein coupled membrane receptors. Indirect evidence of neural or neuroendocrine phenotypes including Inhibitors,Modulators,Libraries high expression of this type of Inhibitors,Modulators,Libraries receptor have been described recently in GISTs. As part of this study, we compiled lists Inhibitors,Modulators,Libraries of differentially expressed genes for comparison with lists of interacting partners of KIT and PDGFR. This analysis identified signif icantly lower expression of PKC alpha and significantly higher expression of PKC theta in tumours with KIT mutations compared to those with PDGFRA Inhibitors,Modulators,Libraries mutations or wild type tumours.

The PKC family consists of 10 related serinethreonine protein kinases, which are involved in regulation of cell proliferation, survival, and death. In addition, KPT-330 order some are considered to be tumour promoters that may enhance multiple cellular oncogenic signalling pathways. While the alpha, beta, epsilon, and atypical PKCs possess anti apoptotic action, the delta and theta isoforms usually promote apoptosis. Interest ingly, PKC theta has been selected previously as a sensi tive marker of GISTs.