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. This evidence concerns the gene LAG3 and cancer.