Disruption of circadian rhythms is closely associated with tumor occurrence and development. This study aims to explore the association between core circadian rhythm genes and the malignant progression of colorectal cancer.

Multiple database resources such as TCGA, Kaplan-Meier Plotter, GEPIA 2.0, TIMER 2.0, cBioPortal, and Methsurv were integrated to systematically analyze the correlation between circadian rhythm genes and the progression of colorectal cancer. Statistical analysis was performed using R 4.3.2 software. Quantitative data that met normal distribution were expressed as (±s), and comparisons between groups were conducted using t tests; quantitative data that did not meet normal distribution or had unequal variances were analyzed using the Wilcoxon rank sum test; count data were expressed as [cases (%)], and were analyzed using the χ² test or Fisher’s exact probability method. P<0.05 indicated statistically significant differences.

Core circadian rhythm genes showed significant differential expression in colorectal cancer and adjacent tissues. Among them, BMAL1, CLOCK, CRY1, NPAS2, NR1D1, and PER1/3 were highly expressed and significantly correlated with poor prognosis in patients (P<0.05). These genes were strongly correlated with APC, and had a weaker association with oncogenes such as MYC, PTEN, and TP53. Additionally, BMAL1/2, CLOCK, CRY1/2, and RORC could affect the infiltration status of immune cells in the tumor microenvironment. High methylation of CRY1, NPAS2, NR1D1, and PER1 indicated poor prognosis, while demethylation of CLOCK and CRY2 had protective effects. Notably, the regulatory role of circadian rhythm genes in colon cancer was more significant than that in rectal cancer, suggesting the existence of tissue-specific regulatory mechanisms.

Circadian rhythm genes can affect the malignant progression of colorectal cancer by regulating proto-oncogenes, immune microenvironment, and DNA methylation status. Moreover, the regulatory role of circadian rhythm genes in the occurrence and development of colon cancer is more significant than that in rectal cancer. Targeted regulation of key genes of circadian rhythm may provide more promising therapeutic strategies for patients with colon cancer.