PIK3CA copy number aberration and activation of the PI3K-AKT-mTOR pathway in varied disease states of penile cancer

Abstract

BackgroundTherapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC).ObjectivesTo determine the prevalence of PIK3CA copy number gain and correlate this with the activity status of PI3K-AKT-mTOR pathway in pre-malignant penile intraepithelial neoplasia (PeIN) and invasive PSCC.Materials and methodsArchival tissue blocks were obtained from 58 PeIN and 244 primary PSCC patients treated at St George’s Hospital. PIK3CA copy number status (CNS) was assessed by fluorescence in-situ hybridisation. High-risk HPV DNA was detected with INNO-LiPA assay. p16INK4A, p-AKT and p-mTOR protein expression were assessed using immunohistochemistry (IHC).ResultsIncreased prevalence of PIK3CA copy number gain was seen in PSCC in comparison to PeIN (84/199 (42%) vs. 10/58 (17%); p = 0.0009). Analysis of the p-AKT and p-mTOR revealed a tendency to a more common expression of cytoplasmic p-AKT (p = 0.1318), nuclear p-AKT (p<0.0001) and cytoplasmic mTOR (p = 0.0006) in PeIN than PSCC. A significant association between p-AKT cytoplasmic immunoexpression and PIK3CA CNS (p = 0.0404) was found in PeIN.ConclusionOverall, PIK3CA copy number gain correlated with activation of the PI3K-AKT-mTOR pathway in PeIN and activation of this pathway is primarily involved in early penile carcinogenesis. Based on these results therapeutic targeting of this pathway in advanced PSCC is unlikely to produce significant clinical benefit. Future studies will need to focus on alternative therapeutic targets.

Post-acute myocardial infarction heart failure core genes and relevant signaling pathways

“…For instance, infiltrating T cells have been shown to affect cardiac lymphatic remodeling, suggesting that immune cells may exert an influence on the progression of post-AMI heart failure. [17][18][19][20][21][22][23] Our study expands on this existing knowledge by identifying 4 specific genes that are strongly correlated with immune cell content in the context of post-AMI heart failure. This unique perspective on the role of these core genes in regulating immune infiltration opens up new possibilities for potential therapeutic targets to prevent and treat post-AMI heart failure by modulating immune responses.…”

“…21 Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a key component of the PI3K-AKT-mTOR pathway involved in cell survival and growth, and its dysregulation has been associated with cardiovascular diseases and cancer. 22 The tumor suppressor gene TP53, often referred to as the guardian of the genome, has numerous roles in cellular processes, including apoptosis and cell cycle control, and its dysregulation has been implicated in various cardiovascular diseases. 23 Of particular interest, SNORD45B exhibited a significant positive correlation with PIK3CA and a significant negative correlation with TP53, indicating potential regulatory interactions between these genes in the context of post-AMI heart failure.…”

“…For instance, infiltrating T cells have been shown to affect cardiac lymphatic remodeling, suggesting that immune cells may exert an influence on the progression of post-AMI heart failure. 17–23…”