BackgroundColon cancer is a common gastrointestinal malignancy. This study aimed to explore the relationship between p53 pathway-related genes and prognosis of colon cancer.MethodsThe mRNA datasets of colon cancer and adjacent tissues were downloaded from The Cancer Genome Atlas (TCGA) database, and the differential expression of genes in two groups was analyzed. Then, P53 pathway-related genes were intersected with differentially expressed genes (DEGs) to obtain P53 pathway-related differentially expressed genes. Then, overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) in clusters were compared by consistent cluster analysis. Univariate and multivariate Cox regression analysis of DEGs was performed to obtain survival-related DEGs. Risk scores were calculated for each sample based on survival-related DEGs, and patients were divided into high/low risk scores. Prognostic differences, tumor immune cell infiltration levels, and immune pathway activation status were compared between the two groups.ResultsWe identified 28 DEGs and two clusters. There are significant differences in PFS between the two clusters (P=0.011), and no significant difference between OS and DSS. We obtained 3 DEGs (CDKN2A, BAK1, BTG1) that were significantly related to PFS, and CDKN2A was considered an independent prognostic factor. PFS showed statistically significant difference between high/low risk score groups (P=0.015). There were significant differences in immune cell infiltration level and immune pathway activity between two groups.ConclusionThe p53 pathway-related genes are significantly related to PFS in colon cancer patients and play an important role in regulating the tumor immune microenvironment.