Abstract
AIM: A systematic review was conducted to summarize the methylated circulating tumor DNA (ctDNA) markers reported over the last decade for early detection of colorectal cancer (CRC) and to identify the main technical challenges that are impeding their clinical implementation. BACKGROUND: CRC is a major cause of cancer deaths worldwide, but early detection is key for successful treatment. Non-invasive methods such as methylated ctDNA testing show promise for improving detection and monitoring of CRC. METHODS: A comprehensive search was performed using Web of Science, PubMed, and Scopus up to December 30, 2023, limited to articles published in the last 10 years (after 2012), while including advanced adenoma/stage 0 or stage I/II samples in biomarker validation. RESULTS: After identifying 694 articles, removing duplicates and screening titles, abstracts, and full texts, a total of 62 articles were found to meet the inclusion criteria. Among the single biomarkers, MYO1-G, SEPT9, SDC2, and JAM3 revealed the highest sensitivity for polyps and stage I/II CRC. For multi-biomarkers with suitable sensitivity, combinations of SFRP1, SFRP2, SDC2, PRIMA1, or ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, VIM or ZFHX4, ZNF334, ELOVL2, UNC5C, LOC146880, SFMBT2, GFRA1 were identified for polyps and stage I/II CRC. CONCLUSION: Enhancing sensitivity and specificity of molecular screening methods is crucial for improving CRC detection. Identifying a select few valuable biomarkers is key to reducing costs, despite challenges posed by low ctDNA levels in plasma, particularly in early-stage cancers.