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Background: Circulating cell-free DNA (cfDNA) in plasma is under investigation as a “liquid biopsy” for monitoring cancers as a surrogate for the primary tumour. The aim of the study was to evaluate the potential of cfDNA for early detection and follow up of patients with colorectal cancers (CRC). Methods: 55 colonic and 29 rectal operable carcinomas were investigated comparing matched tumour tissue and cfDNA. A 69bp ALU repeat qPCR assay was used to quantify fragmented DNA. Allele specific locked nucleic acid/peptide nucleic acid (AS-LNA/PNA qPCR assays were used to detect hot spot mutations in KRAS, BRAF and PIK3CA, optimised using cell lines with known mutation status. Results for cfDNA were compared with clinicopathological features of CRC and overall survival. Results: Total cfDNA levels correlated with disease stage (p=0.003). Cell lines studies demonstrated a limit of mutant DNA detection of 1 genome equivalent (6pg total DNA). Using this threshold, at least one mutation was detected in cfDNA of 40% of cases of CRC. Mutations in cfDNA were more common in colonic cases than rectal cases (p=0.01) and with significantly higher levels of mutant cfDNA (p=0.02).). In colonic tumours, cfDNA levels correlated with tumour stage (p=0.003), size (p=0.04) and LN status (p < 0.005). However, only 6 (86%) with BRAF, 6 (45%) with KRAS and 3 (20%) with PIK3CA matched to the mutations found in the tumour tissue suggesting clonal evolution. PIK3CA mutations were detected for the first time in cfDNA in localised primary tumours including early stage of CRC. Potential use of cfDNA total levels to screen for early lymph nodes involvement demonstrated a ROC of 0.76, with a 75% sensitivity and 86% specificity, suggesting early detection of cancer prior to metastasis. No significant survival differences were observed for cohort cancers for mutant cfDNA. However, mutation in cfDNA of colonic cancers was associated with poor overall survival (p < 0.05). Conclusion: This study has shown that cfDNA has a potential for use as a surrogate for the primary tumour in CRC, and for early detection of colonic cancer prior to metastasis. However, further study in a larger cohort is required to validate these findings.