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Clin Chem. 2016 Aug;62(8):1129-39. doi: 10.1373/clinchem.2015.253609. Epub 2016 Jun 1.

A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker.

Author information

1
Université Paris Sorbonne Cité, INSERM UMR-S1147, CNRS SNC5014, Centre Universitaire des Saints-Pères, Paris Cedex 06, France. Equipe labélisée Ligue contre le cancer;
2
Université Paris Sorbonne Cité, INSERM UMR-S1147, CNRS SNC5014, Centre Universitaire des Saints-Pères, Paris Cedex 06, France. Equipe labélisée Ligue contre le cancer; Department of Digestive Oncology, AP-HP, European Georges Pompidou Hospital, Paris Descartes University, Paris, France;
3
Department of Gastroenterology, Henri-Mondor Hospital-APHP and EA 7375-EC2M3 Laboratory, University of Paris Est Creteil Val de Marne, Creteil, France;
4
Université Paris Sorbonne Cité, INSERM UMR-S1147, CNRS SNC5014, Centre Universitaire des Saints-Pères, Paris Cedex 06, France. Equipe labélisée Ligue contre le cancer; CRB Epigenetec, INSERM UMR-S1147, Centre Universitaire des Saints-Pères, Paris Cedex 06, France;
5
CIC-EC4 URC HEGP, AP-HP, Hôpitaux Universitaires Paris Ouest, Paris, France;
6
INSERM U955, University of Paris Est Creteil Val de Marne and Department of Pathology, AP-HP, Henri-Mondor Hospital, Créteil, France;
7
CRB, AP-HP, Henri-Mondor Hospital, Créteil, France;
8
Service d'hépatogastroentérologie et de cancérologie digestive, CHU de Reims, Hôpital Robert-Debré, Reims Cedex, France;
9
Department of Pathology, Hôpital Ambroise Paré, AP-HP, Université de Versailles St Quentin en Yvelines, Boulogne-Billancourt, France;
10
CHU Clermont Ferrand, Clermont Ferrand Cedex 1, France;
11
Service d'Anatomo-Pathologie, Centre Val d'Aurelle Paul-Lamarque, Montpellier, France;
12
RainDance Technologies, Billerica, MA;
13
Université Paris Sorbonne Cité, INSERM UMR-S1147, CNRS SNC5014, Centre Universitaire des Saints-Pères, Paris Cedex 06, France. Equipe labélisée Ligue contre le cancer; Department of Biology, European Georges Pompidou Hospital, AP-HP, Paris Descartes University, Paris, France. valerie.taly@parisdescartes.fr pierre.laurent-puig@parisdescartes.fr iradj.sobhani@hmn.aphp.fr.
14
Department of Gastroenterology, Henri-Mondor Hospital-APHP and EA 7375-EC2M3 Laboratory, University of Paris Est Creteil Val de Marne, Creteil, France; valerie.taly@parisdescartes.fr pierre.laurent-puig@parisdescartes.fr iradj.sobhani@hmn.aphp.fr.
15
Université Paris Sorbonne Cité, INSERM UMR-S1147, CNRS SNC5014, Centre Universitaire des Saints-Pères, Paris Cedex 06, France. Equipe labélisée Ligue contre le cancer; valerie.taly@parisdescartes.fr pierre.laurent-puig@parisdescartes.fr iradj.sobhani@hmn.aphp.fr.

Abstract

BACKGROUND:

Circulating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies. Droplet-based digital PCR (dPCR) is a highly sensitive and quantitative procedure, allowing detection of very low amounts of circulating tumor genetic material, but can be limited in the total number of target loci monitored.

METHODS:

We analyzed hypermethylation of 3 genes, by use of droplet-based dPCR in different stages of colorectal cancer (CRC), to identify universal markers for tumor follow-up.

RESULTS:

Hypermethylation of WIF1 (WNT inhibitory factor 1) and NPY (neuropeptide Y) genes was significantly higher in tumor tissue compared to normal tissue, independently of tumor stage. All tumor tissues appeared positive for one of the 2 markers. Methylated ctDNA (MetctDNA) was detected in 80% of metastatic CRC and 45% of localized CRC. For samples with detectable mutations in ctDNA, MetctDNA and mutant ctDNA (MutctDNA) fractions were correlated. During follow-up of different stage CRC patients, MetctDNA changes allowed monitoring of tumor evolution.

CONCLUSIONS:

These results indicate that MetctDNA could be used as a universal surrogate marker for tumor follow-up in CRC patients, and monitoring MetctDNA by droplet-based dPCR could avoid the need for monitoring mutations.

PMID:
27251038
DOI:
10.1373/clinchem.2015.253609
[Indexed for MEDLINE]
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