Aging immune system-related blood cell DNA methylation can predict the onset of early stage colorectal cancer

Abstract Objective There is a body of evidence that the aging immune system is linked to cancer. Here, we hypothesized that ubiquitination might play a key gatekeeper role in immune system aging and tumorigenesis in CRC. Therefore, we will systematically study the DNA methylation of ubiquitination genes and screen candidate CRC marker that are correlated with both aging and immune cell compositions. Design Through 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. Then, by collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we used nucleic acid mass spectrometry to test whether ubiquitination genes can be used as candidate markers for the early screening of CRC. Results The biological analyses for aging- and CD4 T cell proportion-derived differential genes showed that they are associated with ubiquitination. Among them, DZIP3 was significantly associated with both aging (P-value = 3.86E-06) and CD4 T cell proportion (P-value = 1.97E-05) in circulating blood. Then, we validated that the 1 st exon DNA methylation of DZIP3 could predict the onset of early stage CRC (AUC = 0.833, OR = 8.82) and all pTNM stages of CRC (AUC = 0.782, OR = 5.70). Conclusions The epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. DNA methylation characteristic of DZIP3 can be used as a promising marker of CRC early screening. Summary box What is already known about this subject? The aging immune system is associated with cancer. Ubiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells. The abnormalities of ubiquitination are closely related to the occurrence of various tumors. Blood cell DNA methylome analysis provides a promising tool to probe the key components of immune cell dysregulation in aging and tumorigenesis. What are the new findings? The aging- and immune cell proportion-derived differential genes are associated with ubiquitination. The epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. DNA methylation characteristic of DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, can be used as a promising markers of CRC early screening. How might it impact on clinical practice in the foreseeable future? The in-depth study for DNA methylome of ubiquitination will open up a new path for the study of CRC pathogenesis, diagnosis and treatment. In addition, DZIP3-focused screening technique only needs to extract the whole blood of individuals for MassARRAY analysis; the samples are easy to obtain, and the results are objective. Therefore, this method may have important applications in clinical CRC screening.