Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer

ObjectiveMutations 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 genom...

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Vydané v:	Gut Ročník 67; číslo 11; s. 1995 - 2005
Hlavní autori:	Barault, Ludovic, Amatu, Alessio, Siravegna, Giulia, Ponzetti, Agostino, Moran, Sebastian, Cassingena, Andrea, Mussolin, Benedetta, Falcomatà, Chiara, Binder, Alexandra M, Cristiano, Carmen, Oddo, Daniele, Guarrera, Simonetta, Cancelliere, Carlotta, Bustreo, Sara, Bencardino, Katia, Maden, Sean, Vanzati, Alice, Zavattari, Patrizia, Matullo, Giuseppe, Truini, Mauro, Grady, William M, Racca, Patrizia, Michels, Karin B, Siena, Salvatore, Esteller, Manel, Bardelli, Alberto, Sartore-Bianchi, Andrea, Di Nicolantonio, Federica
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England BMJ Publishing Group LTD 01.11.2018
Predmet:	Adult Aged Antineoplastic Agents - therapeutic use Biomarkers Biomarkers, Tumor - blood Biomarkers, Tumor - genetics Biopsy Cell Line, Tumor Cell-Free Nucleic Acids - drug effects Cell-Free Nucleic Acids - genetics Cell-Free Nucleic Acids - metabolism Chemotherapy Clinical trials Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Datasets Deoxyribonucleic acid DNA DNA methylation DNA Methylation - genetics DNA microarrays Drug Monitoring - methods Epigenetics Female Gene expression Genomes Humans Longitudinal Studies Male Metastases Metastasis Middle Aged Mutation Oligonucleotide Array Sequence Analysis - methods Patients Pharmacodynamics Polymerase Chain Reaction Population studies Studies Treatment Outcome Tumors screening tumour markers colorectal cancer chemotherapy methylation
ISSN:	0017-5749, 1468-3288, 1468-3288
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Shrnutí:	ObjectiveMutations 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).DesignGenome-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.ResultsMethylation 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.ConclusionThis 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 Co-senior authors
ISSN:	0017-5749 1468-3288 1468-3288
DOI:	10.1136/gutjnl-2016-313372