Patients benefit considerably from early detection of cancer. Existing single-cancer tests have various limitations, which could be effectively addressed by circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED). With sensitive detection and accurate localization of multiple cancer types at a very low and fixed false-positive rate (FPR), MCED has great potential to revolutionize early cancer detection. Herein, we review state-of-the-art approaches for cfDNA-based MCED and their limitations and discuss both technical and clinical challenges in the development and application of MCED tests. Given the constant improvements in technology and understanding of cancer biology, we propose that a cfDNA-based targeted sequencing assay that integrates multimodal features should be optimized for MCED.
Keywords: DNA methylation; cancer screening; circulating cell-free DNA (cfDNA); fragmentomics; multi-cancer early detection (MCED); tissue of origin (TOO).
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