As the mutations imply a change in the hydrophobicity of the aminoacidic residue, #EPZ015938 randurls[1|1|,|CHEM1|]# a functional role cannot be excluded. The mutations were found in MSS cases that did not show any particular feature. We also found that the most common PIK3CA mutation (H1047R) was significantly associated with MSI phenotype. The association

is moderate and would benefit from confirmation on an indipendent series. An association between PIK3CA mutations and MSI has been reported or at least suggested in both colon and stomach cancer [8, 23, 24, 26]. At variance with our findings, in the two studies regarding gastric cancer and reporting mutations by MSI status, exon 9 and exon 20 mutations were evenly distributed between the subtypes [23, 24]. However, the small number of mutated MSI cases prevents statistical comparison. The fact that only one type of mutation was found in our series of MSI tumors

is not surprising as the narrow spectrum of alterations of MSI gastric tumors may, in turn, restrict the type of PIK3CA mutations that are oncogenic in that context. Despite the large series analyzed, we did not find any correlation of PIK3CA mutations with clinical pathological features of gastric cancers apart from the association between MSI and H1047R. The lack of associations suggests that alteration of PIK3CA is an event that occurs early in a subset of gastric cancers that progresses towards malignancy through other mechanisms. In fact, in a multivariate survival model there was no evident

effect of selleck products the presence of mutation on prognosis. Based on our meta-analysis, the ratio between mutation prevalences in exons 9 and 20 can be generally considered a signature of cancer type. In particular, we found a significant exon bias for colon cancer, breast cancer with ductal histotype and endometrium cancer. In colon cancer, exon 9 is significantly Immune system more hit than exon 20. This confirms suggestions from previous studies [8, 23, 27]. The opposite mutational pattern was consistently found in studies regarding endometrial cancer with exon 20 largely more hit than exon 9. This peculiarity was already pointed out and suggests a specific mechanism of PI3KCA involvement for endometrial cancer [28–30]. It is less clear whether an exon bias exists in breast cancer as many studies are apparently contradictory (see Figure 1). However, for studies that did furnish the information about the histotype of each sample, we observed a different exon preference between lobular and ductal histotypes as already suggested [15]. For ductal histotype, exon 20 was significantly more hit compared to exon 9, whereas a slight but inverse tendency was found in series of lobular breast cancers. This pattern is not evident in studies where the information about histotype is not available, possibly as an result of mixing different kinds of tumours together.