mutations have been already identified in a broad range of human cancers at varying frequencies, including liver (36%), breast (26%), colon (25%), urothelial (13%), ovarian (9%), gastric (7%), brain (6%), and lung cancer (2%) as well as leukaemia (1%) 
. The present study adds Merkel cell carcinoma to this list of human cancers harboring PIK3CA
mutations, although in MCC these mutations occur obviously at a low frequency. Both mutations are localized in the helical domain, whereas in most other cancers, mutations in the kinase domain, i.e. in exon 20, are more common (www.sanger.ac.uk/genetics/CGP/cosmic/
). Nevertheless, the E542K mutation is one of the most frequent PIK3CA
hotspot mutations and results in a strong activation of PI3K 
. The E545Q missense mutation is less frequent but has been described in breast, anaplastic thyroid, ovary, and esophageal cancer 
To the best of our knowledge, this is the first report of oncogenic mutations in human MCC. Notably, the analysis of several other oncogenes including HRAS
, and genes of the Wnt pathway did not show any mutations in human MCC 
. Indeed, all of the previously reported mutations in MCC were restricted to tumor suppressor genes. PTEN
mutations were observed at a very low frequency, although loss of heterozygosity at the PTEN
locus at chromosome 10q seems to be a frequent event 
. Similarly, mutations in other tumor suppressor genes such as p53
have been reported, however, only in a very small fraction of MCCs.
Immunohistochemical analysis of the two MCC tumors carrying activating PIK3CA mutations demonstrated a strong AKT phosphorylation; this observation is in line with the fact that these mutations contribute to an activation of the PI3K/AKT signaling pathway. However, the two tumors harboring the activating PIK3CA mutations were not exceptional with respect to AKT pathway activity. In fact, 88% of a series of 41 MCC tissues were classified in the same categories (strong or very strong staining for pAKT T308) suggesting alternative mechanisms (e.g., PTEN alterations) of AKT pathway activation in the majority of cases.
Merkel cell polyomavirus has been recently identified as a widespread virus which upon integration into the genome of MCC precursor cells and acquisition of truncating mutations in the viral large T antigen is likely to contribute to MCC development and progression 
. In this respect we recently demonstrated that MCV infected MCC cells require expression of the MCV T antigens for proliferation and survival 
. MCV genomes encode for the presumably oncogenic large and small T antigens; for the respective homologs encoded by SV40 it has been demonstrated that they can activate the AKT pathway. While for small T this happens via inhibition of the protein phosphatase 2A 
, large T antigen activates the AKT pathway through its interaction with the insulin receptor substrate 1 
. Surprisingly, however, shRNA knock down of both MCV T antigens in infected MCC cell lines did not affect AKT phosphorylation and the lack of correlation between MCV status and AKT phosphorylation in the tumor samples also suggests that the MCV viral T antigens do not contribute to AKT pathway activation in MCC cells, although the significance of the latter observation is impaired by the low number of MCV negative samples. Thus, the presence of the viral proteins seems neither to be sufficient nor necessary for AKT pathway activation in MCC. A very recent report demonstrating that transformation of rodent fibroblasts by MCV small T antigen is independent of PP2A binding further supports that MCV T antigens function different than the related SV40 oncoproteins and that the AKT pathway is not a critical target of MCV T antigens 
. Future studies are warranted to elucidate the molecular mechanisms for AKT pathway activation in MCC.
Since activation of the PI3K/AKT signaling pathway represents one of the most frequent events in human cancer, specific inhibitors of PI3K, AKT and additional components of the PI3K/AKT signaling pathway are currently tested in preclinical and clinical trials 
. Notably, MCC showed a significantly higher AKT phosphorylation than malignant melanoma in our study. In melanoma, phosphorylation of AKT and activation of the PI3K/AKT signaling pathway is a well known feature. A previous study identified AKT phosphorylation in 66% of melanoma samples 
, congruent with the results observed in this study. Consequently, inhibition of the PI3K/AKT pathway by specific inhibitors has evolved as a promising treatment strategy for malignant melanoma 
. In our study, MCC cells showing strong activation of the PI3K/AKT pathway were sensitive to the PI3K inhibitor LY-294002 in vitro
although we cannot exclude that off target effects may contribute to the observed inhibition.
Since metastasized MCC is a very aggressive tumor with poor prognosis and very limited therapeutic options, the presented observations are opening the avenue for targeting the activated PI3K/AKT pathway as an interesting new option for patients suffering from advanced MCC.