A useful mTORC1 signaling-related RiskScore model for the personalized treatment of osteosarcoma patients by using the bulk RNA-seq analysis

Abstract

Abstract Aims This research developed a prognostic model for OS patients based on the Mechanistic Target of Rapamycin Complex 1 (mTORC1) signature. Background The mTORC1 signaling pathway has a critical role in the maintenance of cellular homeostasis and tumorigenesis and development through the regulation of cell growth, metabolism and autophagy. However, the mechanism of action of this signaling pathway in Osteosarcoma (OS) remains unclear. Objective The datasets including the TARGET-OS and GSE39058, and 200 mTORC1 genes were collected. Methods The mTORC1 signaling-related genes were obtained based on the Molecular Signatures Database (MSigDB) database, and the single sample gene set enrichment analysis (ssGSEA) algorithm was utilized in order to calculate the mTORC1 score. Then, the WGCNA were performed for the mTORC1-correlated gene module, the un/multivariate and lasso Cox regression analysis were conducted for the RiskScore model. The immune infiltration analysis was performed by using the ssGSEA method, ESTIMATE tool and MCP-Count algorithm. KM survival and Receiver Operating Characteristic (ROC) Curve analysis were performed by using the survival and timeROC package. Results The mTORC1 score and WGCNA with β = 5 screened the mTORC1 positively correlated skyblue2 module that included 67 genes, which are also associated with the metabolism and hypoxia pathways. Further narrowing of candidate genes and calculating the regression coefficient, we developed a useful and reliable RiskScore model, which can classify the patients in the training and validation set into high and low-risk groups based on the median value of RiskScore as an independent and robust prognostic factor. High-risk patients had a significantly poor prognosis, lower immune infiltration level of multiple immune cells and prone to cancer metastasis. Finally, we a nomogram model incorporating the metastasis features and RiskScore showed excellent prediction accuracy and clinical practicability. Conclusion We developed a useful and reliable risk prognosis model based on the mTORC1 signaling signature.

Keywords

• Osteosarcoma (OS)
• MTORC1 signaling signature
• RiskScore
• Tumor microenvironment
• Weighted Gene Co-expression Network Analysis (WGCNA)
• Lasso