Secondly, our research results are based on a case–control study and cannot provide confirmation that whether abnormal changes of methylation statuses of PDCD-1 and LAG-3 are the preparatory epigenetic event of CRC or cancer-derived consequences; However, the GSE51032 dataset is from a nested case–control study of the prospective EPIC-Italy cohort (Cordero et al. 2015), in which the blood samples were collected 74.1 months (range from 0.2 to 172.8 months) prior to CRC diagnosis. The gene discussed is PDCD1; the disease is cancer.