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

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 TruiniWilliam M. Grady, Patrizia Racca, Karin B. Michels, Salvatore Siena, Manel Esteller, Alberto Bardelli, Andrea Sartore-Bianchi, Federica Di Nicolantonio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1995-2005
Number of pages11
JournalGut
Volume67
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

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Keywords

  • chemotherapy
  • colorectal cancer
  • methylation
  • screening
  • tumour markers

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Barault, L., Amatu, A., Siravegna, G., Ponzetti, A., Moran, S., Cassingena, A., Mussolin, B., Falcomatà, C., Binder, A. M., Cristiano, C., Oddo, D., Guarrera, S., Cancelliere, C., Bustreo, S., Bencardino, K., Maden, S., Vanzati, A., Zavattari, P., Matullo, G., ... Di Nicolantonio, F. (2018). Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer. Gut, 67(11), 1995-2005. https://doi.org/10.1136/gutjnl-2016-313372