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

ObjectiveThere 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. DesignThrough 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. ResultsThe 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 1st 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). ConclusionsThe 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 boxO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIThe aging immune system is associated with cancer. C_LIO_LIUbiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells. C_LIO_LIThe abnormalities of ubiquitination are closely related to the occurrence of various tumors. C_LIO_LIBlood cell DNA methylome analysis provides a promising tool to probe the key components of immune cell dysregulation in aging and tumorigenesis. C_LI What are the new findings?O_LIThe aging- and immune cell proportion-derived differential genes are associated with ubiquitination. C_LIO_LIThe epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. C_LIO_LIDNA 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. C_LI How might it impact on clinical practice in the foreseeable future?O_LIThe in-depth study for DNA methylome of ubiquitination will open up a new path for the study of CRC pathogenesis, diagnosis and treatment. C_LIO_LIIn 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. C_LI