Identification and validation of a necroptosis-related gene prognostic signature for colon adenocarcinoma.

ABSTRACT

Background: Necroptosis is a novel programmed cell death pathway proposed in 2005, which is mainly activated by the tumor necrosis factor (TNF) family and mediates cellular disassembly via receptor interacting serine/threonine kinase 1 (RIPK1), receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL). We tried to analyze the relationship of necroptosis-related genes (NRGs) expression with colon adenocarcinoma (COAD) and propose potential therapeutic targets through immunological analysis. Methods: First, we evaluated the expression of NRGs in COAD patients and constructed a prognostic signature. The prognostic signature was validated using The Cancer Genome Atlas (TCGA)-COAD and GSE39582 datasets, respectively. And the Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and principal component analysis were used to evaluate the signature. Then we analyzed the enrichment of NRGs in the signature using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, we analyzed the immunological characteristics of the COAD patients by single sample gene set enrichment analysis (ssGSEA) and predicted the possible immune checkpoints. Results: We constructed a prognostic signature with 8 NRGs (RIPK3, MLKL, TRAF2, CXCL1, RBCK1, CDKN2A, JMJD7-PLA2G4B and CAMK2B). The Kaplan-Meier analysis, ROC curves, and principal component analysis demonstrated good predictivity of the signature. In addition, we constructed a nomogram with good individualized predictive ability (C-index =0.772). The immunological analysis revealed that the prognosis of COAD was associated with autoimmune function, and we proposed 10 potential therapeutic targets. Conclusions: Overall, we constructed an NRGs prognostic signature and suggested potential therapeutic targets for the COAD treatment.