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These tests have the potential to overcome barriers to screening. This review evaluates the current evidence to better understand their utility for routine screening. The authors searched PubMed, other databases, and gray literature sources through March 30, 2026. Included studies examined the diagnostic accuracy, harms, and the adherence to cfDNA and mt\u2010sRNA screening tests for colorectal cancer (CRC). One investigator abstracted data, and a second confirmed. Two investigators independently assessed the risk of bias and strength of evidence. Discords were resolved through consensus. From 262 titles, 12 studies (17 publications) were included. Three studies provide moderate strength evidence to support the performance characteristics of cfDNA, and one provides low strength evidence for mt\u2010sRNA. For cfDNA, adjusted CRC and advanced precancerous lesions sensitivities ranged from 80.8% to 81.1% and from 12.9% to 13.7%, respectively, and advanced colorectal neoplasia specificity ranged from 89.5% to 90.4%. For mt\u2010sRNA, CRC sensitivities were 93% and 48%, and observed specificity was 90%. No studies reported serious harms, and the evidence comparing adherence was insufficient. We found that cfDNA screening tests for CRC are similar, and although mt\u2010sRNA estimates fall below those demonstrated by mt\u2010sDNA, its in\u2010laboratory fecal immunochemical testing, has the potential to increase adherence. Future research examining adherence is needed, as are data from which to examine their impact on underrepresented populations.<\/jats:p>","DOI":"10.1002\/cncr.70428","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:07:55Z","timestamp":1779880075000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Blood\u2010based cell\u2010free DNA and multitarget stool RNA screening tests to detect colorectal cancer: A systematic review"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4635-5056","authenticated-orcid":false,"given":"Karli K.","family":"Kondo","sequence":"first","affiliation":[{"name":"Center for Early Cancer Detection American Cancer Society  Atlanta Georgia USA"},{"name":"Research Integrity Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-1827","authenticated-orcid":false,"given":"Rita L.","family":"Shiau","sequence":"additional","affiliation":[{"name":"Center for Early Cancer Detection American Cancer Society  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1570-2258","authenticated-orcid":false,"given":"Clarissa A. 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