Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer
Year: 2017
Type: article
Study design: Observational Study
Abstract: 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.
Source: Gut
Authors: Ludovic Barault, Alessio Amatu, Giulia Siravegna, Agostino Ponzetti, Sebastian Moran, Andrea Cassingena, Benedetta Mussolin, Chiara Falcomatà, Alexandra M Binder, Carmen Cristiano, Daniele Oddo, Simonetta Guarrera, Carlotta Cancelliere, Sara Bustreo, Katia Bencardino, Sean Maden, Alice Vanzati, Patrizia Zavattari, Giuseppe Matullo, Mauro Truini, William M Grady, Patrizia Racca, Karin B Michels, Salvatore Siena, Manel Esteller, Alberto Bardelli, Andrea Sartore-Bianchi, Federica Di Nicolantonio
Institutions: Candiolo Cancer Institute, University of Turin, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, IFOM, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, Azienda Ospedaliero Universitaria San Giovanni Battista, Institut d'Investigació Biomédica de Bellvitge, University of California, Los Angeles, Italian institute for Genomic Medicine, Fred Hutch Cancer Center, University of Cagliari, University of Washington, University of Milan, Institució Catalana de Recerca i Estudis Avançats, Universitat de Barcelona
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funders: Merck, Fondazione Banco di Sardegna, Ministero della Salute, Ministero dell’Istruzione, dell’Università e della Ricerca, Fondazione Umberto Veronesi, Associazione Italiana per la Ricerca sul Cancro, Università degli Studi di Torino, Regione Autonoma della Sardegna, Innovative Medicines Initiative, Fondazione Oncologia Niguarda Onlus, National Institutes of Health, Horizon 2020 Framework Programme, National Cancer Institute, H2020 European Institute of Innovation and Technology, FP7 Ideas: European Research Council
Awards: G1021298972, Discovery and verification of novel biomarkers of colorectal cancer recurrence, G188822558, G3893518518, (PQC1) Accelerated biological aging and colon polyp to cancer progression, G5079323043, G6007495210, Biomarkers for Reducing Mortality of Cancers of the Colon and Esophagus, G6263909264, G6981174239, G7729809375, G8713105198, G8990289309, UW Comprehensive Cancer Center Support, Cancer Center Support Grant
OpenAlex ID: W2760986701