Core Viewpoint - Colorectal cancer (CRC) is the third most common cancer globally, with nearly 2 million new cases annually, and the second leading cause of cancer-related deaths, claiming nearly 1 million lives each year. The study published by Wuhan University researchers identifies a significant single nucleotide mutation (rs10871066) associated with increased risk of precancerous lesions and colorectal cancer, revealing underlying oncogenic mechanisms [2][5]. Group 1 - The research utilized multi-omics data from 533 colorectal tissue samples, ranging from normal tissues to early adenomas and cancers, to establish a dynamic epigenetic map [5]. - A total of 7,492 differential cis-regulatory elements (CREs) were identified, linked to 5,490 target genes [5]. - High-throughput CRISPR interference (CRISPRi) screening revealed 265 functional CREs associated with colorectal cancer cell proliferation [5]. Group 2 - A polygenic risk score (PRS) model based on functional CRE mutations effectively predicted colorectal cancer and precancerous lesions in 476,770 individuals [5]. - The functional mutation rs10871066 is significantly correlated with increased risk of precancerous lesions and colorectal cancer [5]. - Mechanistically, rs10871066 mediates the conversion from silencers to enhancers through FOXP1 and TCF7L2, leading to the upregulation of KLF5 and activation of oncogenic pathways, while also upregulating PIBF1 to inhibit natural killer (NK) cell cytotoxicity [5].