A gene signature related to programmed cell death to predict immunotherapy response and prognosis in colon adenocarcinoma.

BACKGROUND: Tumor development involves the critical role of programmed cell death (PCD), but the correlation between colon adenocarcinoma (COAD) and PCD-related genes is not clear. METHODS: Subtyping analysis of COAD was performed by consensus clustering based on The Cancer Genome Atlas (TCGA), with the AC-ICAM queue from the cBioportal database as a validation set. Immune infiltration of the samples was evaluated using CIBERSORT and Microenvironment Cell Populations (MCP)-counter algorithms. Patients' immunotherapy response was predicted by the TIDE and aneuploidy scores. Pathway enrichment analysis was conducted with gene set enrichment analysis (GSEA). A RiskScore model was established with independent prognostic PCD-related genes filtered by Cox regression analysis. The mafCompare function was used to compare the differences in mutation rates of somatic genes. Wound healing, transwell assays and Flow cytometer were applied to measure the cell migration, invasion and apoptosis. RESULTS: The patients were grouped into S1 and S2 subtypes based on a total of 21 PCD genes associated with the prognostic outcomes of COAD. Specifically, patients of S1 subtype were mainly related to the pathway activation in tumor invasion and deterioration and had a worse prognosis. A RiskScore model was established based on six prognostic genes, including two protective genes (ATOH1, ZG16) and four risk genes (HSPA1A, SEMA4C, CDKN2A, ARHGAP4). Notably, silencing of CDKN2A inhibited the activity of migration and invasion and promoted apoptosis of tumor cells. Based on the RiskScore model, the patients were grouped into high- and low-risk groups. Independent prognostic factors, namely, Age, pathologic_M, pathologic_stage, and RiskScore, were integrated to develop a nomogram with strong good prediction performance. High-risk group had high-expressed immune checkpoint genes and higher TIDE scores, showing a strong immune escape ability and less active immunotherapy response. Compared to the low-risk group, TP53 exhibited a higher rate of somatic mutation in the high-risk group. CONCLUSION: We constructed a RiskScore model with six PCD-related genes for the prognostic assessment of COAD, providing a valuable insight into the exploration of new targets for the prognostic improvement in COAD.