Methylation biomarkers for early detection of colorectal cancer: From molecular discovery to clinical translation and application

ABSTRACT Due to high morbidity and mortality rates, colorectal cancer (CRC) poses the significant global health challenge, thus early screening is essential to improve patient outcomes. DNA methylation biomarkers have become pivotal tools for detection of CRC, moving from research to clinical use. Key methylation loci (SEPT9, BMP3, and NDRG4) have been identified through genome-wide association studies and candidate gene approaches, then validated with high-throughput technologies, such as methylation arrays and next-generation sequencing. This advancement has led to the creation of clinically approved assays. Notably, the sensitivity of the Cologuard assay for detection of CRC is 92%, while that of the Epi proColon assay is 70%–80%, both outperforming traditional methods like fecal immunochemical testing, which has a sensitivity of 74%. These assays offer non-invasive screening for both average- and high-risk groups, and aid in postoperative monitoring. However, significant challenges remain. Key issues include technical difficulties for detection of low-abundance methylation signals and standardization of sample processing methods. Clinically, managing false results and validating long-term efficacy are problematic. Ethical concerns about overdiagnosis and data privacy also require attention. Future efforts should prioritize technological advancements, like single-molecule sequencing and liquid biopsy integration, along with large-scale prospective studies to validate biomarker utility in diverse populations. Updated guidelines for standardized implementation are also crucial. This review underscores the pivotal role of methylation biomarkers to revolutionize screening of CRC, while stressing the need for interdisciplinary collaboration, and outlines a strategy to address current limitations, ultimately aiming to reduce the global impact of CRC.