Abstract
Colorectal cancer (CRC) remains a major cause of cancer incidence and mortality worldwide. Because colonoscopy is resource-intensive and participation is incomplete, non-invasive screening tests are central to population-level prevention. This review synthesizes recent evidence on fecal immunochemical testing (FIT), multi-omics stool DNA-FIT (mt-sDNA-FIT), multi-omics stool RNA-FIT (mt-sRNA-FIT), and blood-based assays, with emphasis on screening of asymptomatic individuals at average risk, the distinction between cancer detection and advanced precancerous lesion detection, and the operational requirements needed to translate test performance into public health benefit. FIT remains the most scalable first-line option in many programs because it is inexpensive, repeatable, and supported by evidence from organized screening. Its performance depends on hemoglobin threshold, sampling and handling, lesion biology, repeated adherence, and colonoscopy completion after a positive result. Molecular stool assays generally improve single-application sensitivity for CRC and advanced precancerous lesions but reduce specificity and increase costs and demand for colonoscopy. Blood-based assays may improve acceptability among people who decline stool testing or colonoscopy; however, current evidence indicates reduced detection of advanced precancerous lesions, limiting their preventive value when used as direct replacements for stool-based strategies. Implementation barriers occur across the screening pathway, including invitation, test access, sample return, laboratory processing, result communication, diagnostic colonoscopy, pathology, treatment access, and registry tracking. Future progress should prioritize risk-adapted screening, validated molecular and multiomics biomarkers, and artificial intelligence-assisted triage, and equitable program design. The most defensible strategy is not universal adoption of a single assay but a resource-stratified pathway that matches screening modality to population risk, patient acceptability, and system capacity.