Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer

BACKGROUND: Necroptosis, is intimately linked to tumor development and prognosis and has been considered as a target for anticancer therapy. However, the role of necroptosis-related genes (NRGs) in colon cancer is unclear. METHODS: In the present study, we screened 76 NRGs from previous studies and described the landscape of transcriptomic and genetic variation of NRGs in colon cancer (CC) patient samples. Molecular subtypes of necroptosis in colon cancer were identified by clustering analysis, and these molecular subtypes were linked to patient prognosis and TME cell infiltration characteristics. Then, the NRS-score for predicting overall survival (OS) was built based on the TCGA database and validated in the GSE39582 cohort for its predictive power in CC patients. Besides, the ESTIMATE and CIBERSORT algorithms were applied to explore the relationship between NRS-score and tumor immune microenvironment. RESULTS: We identified two molecular subtypes associated with necroptosis in CC, which have diverse prognosis and immune microenvironment characteristics. Based on the differentially expressed genes between the two molecular subtypes, we further developed a necroptosis risk score signature, referred to as NRS-score. High NRS-score was associated with poor prognosis in CC through immunosuppressive microenvironment and immune escape mechanisms. The nomogram based on NRS-score showed excellent ability to predict prognosis. In addition, NRS-score presented a positive correlation with tumor mutational burden (TMB) and immune checkpoint blockade (ICB) expression and was closely correlated with multiple anticancer agent susceptibility. CONCLUSION: This work revealed a close relationship between necroptosis and the prognosis and immune microenvironment of colon cancer. The NRS-score based on the 8-gene signature may be used to predict the sensitivity of immunotherapy and chemotherapy in colon cancer patients, and provides a foundation for future studies targeting necroptosis and its immune microenvironment.