Cluster B2 consists of all pediatric and sixteen adult WT gastric cases which can be further split selleck chem Dorsomorphin into Clusters B2a and B2b. All known Carney triad cases cluster together in B2b, which could also contain cases not yet definitively diagnosed as Carney triad at the time of writing (n=4). In the dyad, paraganglioma is typically the first tumor manifestation, with GIST following, however in Carney triad, generally GIST is the first tumor diagnosed and it can take many years for other tumors [pulmonary chondroma and paraganglioma] to develop, so that the diagnosis of Carney triad may be delayed by years or even decades. The miRNAs differentially expressed between Clusters B2a and B2b therefore may represent a signature that could prompt closer patient monitoring for development of additional tumor manifestations of Carney triad compared to those patients in Cluster B2a.

A larger cohort with retrospective clinical data is required for confirmation of such a theory. Thirty-four miRNAs are differentially expressed between the Clusters B2a and B2b. Some of these, including let-7g, miR-212 and miR-132 are known to target c-MYC [56], Rb1 [32] and RASA1 [57] respectively, in various other tumors. The heatmap following removal of the dominant 14q cluster (Figure 2) still clearly shows that the adult WT cases are dispersed between adult mutant and pediatric cases and this is apparently on the basis of SDHB reactivity. It has emerged recently that SDHB immunoreactivity is tightly correlated with mutational status in GIST such that mutant cases are consistently SDHB-immunopositive while WT cases are frequently SDHB-immunonegative, notably in the pediatric setting [13], [14].

A result which parallels ours, has recently been identified by Killian et al [58] showing that WT GISTs demonstrating a ��methyl centrist�� profile (a methylation pattern which resembles that of normal tissues) were all positive for SDHB immunohistochemically and had clinical characteristics similar to mutant GISTs with greater tyrosine kinase inhibitor response, while WT GISTs within the ��methyl divergent�� group (cases showing an outlier methylation pattern relative to normal tissues and mutant GIST samples) were all negative for SDHB by immunohistochemistry and behaved clinically similarly to pediatric GISTs.

Both of these epigenetic studies �Cthe Killian et al methylation data and our miRNA profiling -have therefore separated adult WT GISTs based on their SDHB immunohistochemistry status, placing SDHB-immunopositive WT GISTs with adult mutant GISTs, a finding which raises the tantalising possibility that these tumors bear yet-to-be identified Dacomitinib oncogenic kinase mutations. Such a pattern is observed not only for gastric adult WT GISTs, but particularly also for those cases arising in small bowel and retroperitoneum in our cohort.