Review of Blood-Based Colorectal Cancer Screening: How Far Are Circulating Cell-Free DNA Methylation Markers From Clinical Implementation?

Colorectal cancer (CRC) is a leading cause of cancer related deaths worldwide, and late stages (III-IV) in particular have low 5-year survival rates. Stage shifting by CRC screening programs has proven effective by decreasing morbidity and mortality and in many countries national CRC screening programs have been implemented. Currently, European, Asian, and American authorities recommend screening for CRC using fecal occult blood testing, sigmoidoscopy, or colonoscopy. Because these approaches all have weaknesses (eg, poor compliance, high costs, test invasiveness), much effort has been put into the development of alternative screening approaches, many of which are blood-based. Blood-based strategies especially present the advantages of minimally invasiveness compared to endoscopies and an expectantly higher compliance rate compared to stool-based tests. The last decades have seen many discovery studies identifying promising blood-based biomarkers of CRC; however, common to all of these markers is that their clinical usefulness remains evasive. At present only one blood-based CRC screening marker has been approved in the United States. The aim of this review is to discuss the development of blood-based cell-free DNA methylation marker candidates for CRC screening. On the basis of a methodical literature search, the past, present, and future of cell-free DNA screening markers for CRC are revised and discussed. Resource limitations and technical challenges related to sensitivity and specificity measurements keep many markers at bay. Possible solutions to these problems are offered to enable markers to benefit future screening participants.