Colorectal cancer marker identification using the aging immune system-related blood cell DNA methylome

There is a body of evidence that the aging immune system is linked to cancer. In this study, with aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune cell proportion in the circulating whole blood of healthy individuals. The biological analyses for aging- and CD4 T cell proportion-derived differential genes showed that ubiquitination plays an important role in the aging immune system and tumorigenesis. Among the differentially ubiquitinated genes, DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, was significantly associated with both aging (P-value = 3.86E-06) and CD4 T cell proportion (P-value = 1.97E-05) in circulating blood. By collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we validated that the 1 exon DNA methylation of DZIP3 could predict the onset of early stage colorectal cancer (AUC = 0.833, OR = 8.82) and all pTNM stages of colorectal cancer (AUC = 0.782, OR = 5.70). Thus, the epigenetically regulated ubiquitination machine plays an important role in immune aging and tumorigenesis.