Development and Validation of a Novel Survival Model for Cutaneous Melanoma Based on Necroptosis-Related Genes

Abstract

BackgroundNecroptosis is crucial for organismal development and pathogenesis. To date, the role of necroptosis in skin cutaneous melanoma (SKCM) is yet unveiled. In addition, the part of melanin pigmentation was largely neglected in the bioinformatic analysis. In this study, we aimed to construct a novel prognostic model based on necroptosis-related genes and analysis the pigmentation phenotype of patients to provide clinically actionable information for SKCM patients.MethodsWe downloaded the SKCM data from the TCGA and GEO databases in this study and identified the differently expressed and prognostic necroptosis-related genes. Patients’ pigmentation phenotype was evaluated by the GSVA method. Then, using Lasso and Cox regression analysis, a novel prognostic model was constructed based on the intersected genes. The risk score was calculated and the patients were divided into two groups. The survival differences between the two groups were compared using Kaplan-Meier analysis. The ROC analysis was performed and the area under curves was calculated to evaluate the prediction performances of the model. Then, the GO, KEGG and GSEA analyses were performed to elucidate the underlying mechanisms. Differences in the tumor microenvironment, patients’ response to immune checkpoint inhibitors (ICIs) and pigmentation phenotype were analyzed. In order to validate the mRNA expression levels of the selected genes, quantitative real-time PCR (qRT-PCR) was performed.ResultsAltogether, a novel prognostic model based on four genes (BOK, CD14, CYLD and FASLG) was constructed, and patients were classified into high and low-risk groups based on the median risk score. Low-risk group patients showed better survival status. The model showed high accuracy in the training and the validation cohort. Pathway and functional enrichment analysis indicated that immune-related pathways were differently activated in the two groups. In addition, immune cells infiltration patterns and sensitivity of ICIs showed a significant difference between patients from two risk groups. The pigmentation score was positively related to the risk score in pigmentation phenotype analysis.ConclusionIn conclusion, this study established a novel prognostic model based on necroptosis-related genes and revealed the possible connections between necroptosis and melanin pigmentation. It is expected to provide a reference for clinical treatment.

Construction and validation model of necroptosis-related gene signature associates with immunity for osteosarcoma patients

“…In addition to the above pathway processes, some immune-related pathways, such as Th17 cell differentiation also enriched. These results also focus on apoptosis and inflammation, consistent with our findings, compared with NRGs functional enrichment in other tumors 20 , 48 , 49 . These results demonstrate that osteosarcoma and normal tissue differ in genes associated with cell death and contribute to activating inflammatory, apoptotic and necroptosis signaling pathways.…”

“…However, NRGs have been reported to influence the tumor microenvironment 47 , 48 . In addition, tumor microenvironment and immune cells have influenced prognosis in different tumors 49 , 50 . Additionally, univariate and multivariate Cox regression analyses were performed to investigate the effects of other clinical indicators, such as age, sex, metastasis and NRG risk score, on tumor prognosis.…”

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“…To evaluate which group was more applicable for immunotherapy, several immune checkpoint genes [ 23 ] and IPS were introduced for investigation. As depicted in Figure 8(a) , the expression of immune checkpoint genes was substantially upregulated in exception to programmed cell death 1 ligand 1 (PD-L1) in the high ICS score group.…”

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