Ke J, Tian J, Mei S, et al. - Given dozens of loci related to colon and rectal adenocarcinoma risk have been found through genome-wide association studies (GWAS), and since tissue-specific super-enhancers (SE) have crucial roles in tumorigenesis, researchers systematically examined SEs and inner variants in established GWAS loci to explain the underlying biological mechanisms. They screened potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, using multi-omics data, and thereafter subjected them to a two-stage case–control analyis including 4,929 cases and 7,083 controls from the Chinese population. A significant link of the SNP rs11064124 in 12p13.31 with the risk of colon and rectal adenocarcinoma was identified with an odds ratio of 0.87. The actions of protective rs11064124-G included weakening of the binding affinity with vitamin D receptor and raising the enhancer's activity as well as interactions with two target genes' promoters, thereby ultimately coactivating the transcription of CD9 and PLEKHG6 (putative tumor suppressor genes for colon and rectal adenocarcinoma). Findings revealed a SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma.