TY - JOUR T1 - Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer JF - Gut JO - Gut SP - 1995 LP - 2005 DO - 10.1136/gutjnl-2016-313372 VL - 67 IS - 11 AU - Ludovic Barault AU - Alessio Amatu AU - Giulia Siravegna AU - Agostino Ponzetti AU - Sebastian Moran AU - Andrea Cassingena AU - Benedetta Mussolin AU - Chiara Falcomatà AU - Alexandra M Binder AU - Carmen Cristiano AU - Daniele Oddo AU - Simonetta Guarrera AU - Carlotta Cancelliere AU - Sara Bustreo AU - Katia Bencardino AU - Sean Maden AU - Alice Vanzati AU - Patrizia Zavattari AU - Giuseppe Matullo AU - Mauro Truini AU - William M Grady AU - Patrizia Racca AU - Karin B Michels AU - Salvatore Siena AU - Manel Esteller AU - Alberto Bardelli AU - Andrea Sartore-Bianchi AU - Federica Di Nicolantonio Y1 - 2018/11/01 UR - http://gut.bmj.com/content/67/11/1995.abstract N2 - Objective Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).Design Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy.Results Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival.Conclusion This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations. ER -