Clinical Implications of Necroptosis Genes Expression for Cancer Immunity and Prognosis: A Pan-Cancer Analysis. Frontiers in immunology Background:Necroptosis, a form of programmed cell death, is increasingly being investigated for its controversial role in tumorigenesis and progression. Necroptosis suppresses tumor formation and tumor development by killing tumor cells; however, the necrotic cells also promote tumor formation and tumor development the immunosuppressive effect of necroptosis and inflammatory response caused by cytokine release. Thus, the exact mechanism of necroptosis in pan-cancer remains unknown. Methods:The data of 11,057 cancer samples were downloaded from the TCGA database, along with clinical information, tumor mutation burden, and microsatellite instability information of the corresponding patients. We used the TCGA data in a pan-cancer analysis to identify differences in mRNA level as well as single nucleotide variants, copy number variants, methylation profiles, and genomic signatures of miRNA-mRNA interactions. Two drug datasets (from GDSC, CTRP) were used to evaluate drug sensitivity and resistance against necroptosis genes. Results:Necroptosis genes were aberrantly expressed in various cancers. The frequency of necroptosis gene mutations was highest in lung squamous cell carcinoma. Furthermore, the correlation between necroptosis gene expression in the tumor microenvironment and immune cell infiltration varied for different cancers. High necroptosis gene expression was found to correlate with NK, Tfh, Th1, CD8_T, and DC cells. These can therefore be used as biomarkers to predict prognosis. By matching gene targets with drugs, we identified potential candidate drugs. Conclusion:Our study showed the genomic alterations and clinical features of necroptosis genes in 33 cancers. This may help clarify the link between necroptosis and tumorigenesis. Our findings may also provide new approaches for the clinical treatment of cancer. 10.3389/fimmu.2022.882216

A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs. Frontiers in immunology Background:Necroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients with hepatocellular carcinoma, and to find potentially effective drugs. Methods:The three algorithms ssGSEA, EPIC, and ESTIMATE were used to quantify the immune cell infiltration of the samples, differentially expressed genes (DEGs) analysis, and weighted gene co-expression network analysis were used to screen necroptosis related genes. Variables were screened according to random survival forest analysis, and combinations with significant p-values and a low number of genes were defined as prognostic signatures by using log-rank test after gene combination. Based on the sensitivity data of PRISM and CTRP2.0 datasets, we predicted the potential therapeutic agents for high-NRS patients. Results:Seven genes such as TOP2A were used to define necroptosis-related risk score (NRS). The prognostic value of risk score was further validated, where high NRS was identified as a poor prognostic factor and tended to have higher grades of histologic grade, pathologic stage, T stage, BCLC, CLIP, and higher AFP. Higher NRS was also negatively correlated with the abundance of DCs, Neutrophils, Th17 cells, Macrophages, Endothelial, and positively correlated with Th2 cells. Necroptosis is often accompanied by the release of multiple cytokines, and we found that some cytokines were significantly correlated with both NRS and immune cells, suggesting that necroptosis may affect the infiltration of immune cells through cytokines. In addition, we found that TP53 mutations were more common in samples with high NRS, and these mutations may be associated with changes in NRS. Patients with high NRS may be more sensitive to gemcitabine, and gemcitabine may be an effective drug to improve the prognosis of patients with high NRS, which may play a role by inhibiting the expression of TOP2A. Conclusions:We constructed a necroptosis-related scoring model to predict OS in HCC patients, and NRS was associated with immune response, TP53 mutation, and poor clinical classification in HCC patients. In addition, gemcitabine may be an effective drug for high-NRS patients. 10.3389/fimmu.2022.870264

Necroptosis-related lncRNA to establish novel prognostic signature and predict the immunotherapy response in breast cancer. Journal of clinical laboratory analysis BACKGROUND:Necroptosis is a type of programmed cell death, and recent researches have showed that lncRNAs could regulate the process of necroptosis in multiple cancers. We tried to screen necroptosis-related lncRNAs and investigate the immune landscape in breast cancer (BC). METHODS:The samples of breast normal and cancer tissue were acquired from TCGA and GTEx databases. A risk prognostic model was constructed based on the identified necroptosis-related lncRNAs by Cox regression and least absolute shrinkage and selection operator (LASSO) method. Moreover, the forecast performance of this model was verified and accredited by synthetic approach. Subsequently, an accurate nomogram was constructed to predict the prognosis of BC patients. The biological differences were investigated through GO, GSEA, and immune analysis. The immunotherapy response was estimated through tumor mutation burden (TMB) and tumor immune dysfunction and exclusion (TIDE) score. RESULTS:A total of 251 necroptosis-related lncRNAs were identified by differential coexpression analysis, and SH3BP5-AS1, AC012073.1, AC120114.1, LINC00377, AL133467.1, AC036108.3, and AC020663.2 were involved in the risk model, which had an excellent concordance with the prediction. The pathway analyses showed that immune-related pathways were relevant to the necroptosis-related lncRNAs risk model. And the risk score was significantly correlated with immune cell infiltration, as well as the ESTIMATE score. Most notably, the patients of higher risk score were characterized with increased TMB and decreased TIDE score, indicating that these patients showed better immune checkpoint blockade response. CONCLUSION:These findings were conducive to understand the function of necroptosis-related lncRNAs in BC and provide a potential promising therapeutic strategy for BC. 10.1002/jcla.24302