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      Is Open Access

      High Fragmentation Characterizes Tumour-Derived Circulating DNA

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          Abstract

          Background

          Circulating DNA (ctDNA) is acknowledged as a potential diagnostic tool for various cancers including colorectal cancer, especially when considering the detection of mutations. Certainly due to lack of normalization of the experimental conditions, previous reports present many discrepancies and contradictory data on the analysis of the concentration of total ctDNA and on the proportion of tumour-derived ctDNA fragments.

          Methodology

          In order to rigorously analyse ctDNA, we thoroughly investigated ctDNA size distribution. We used a highly specific Q-PCR assay and athymic nude mice xenografted with SW620 or HT29 human colon cancer cells, and we correlated our results by examining plasma from metastatic CRC patients.

          Conclusion/Significance

          Fragmentation and concentration of tumour-derived ctDNA is positively correlated with tumour weight. CtDNA quantification by Q-PCR depends on the amplified target length and is optimal for 60–100 bp fragments. Q-PCR analysis of plasma samples from xenografted mice and cancer patients showed that tumour-derived ctDNA exhibits a specific amount profile based on ctDNA size and significant higher ctDNA fragmentation. Metastatic colorectal patients (n = 12) showed nearly 5-fold higher mean ctDNA fragmentation than healthy individuals (n = 16).

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          Most cited references25

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          American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy.

          Carmen J Allegra, J. Milburn Jessup, Mark Somerfield … (2009)
          An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status. Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.
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            Circulating nucleic acids (CNAs) and cancer--a survey.

            M Fleischhacker, B. Schmidt (2006)
            It has been known for decades that it is possible to detect small amounts of extracellular nucleic acids in plasma and serum of healthy and diseased human beings. The unequivocal proof that part of these circulating nucleic acids (CNAs) is of tumor origin, initiated a surge of studies which confirmed and extended the original observations. In the past few years many experiments showed that tumor-associated alterations can be detected at the DNA and RNA level. At the DNA level the detection of point mutations, microsatellite alterations, chromosomal alterations, i.e. inversion and deletion, and hypermethylation of promoter sequences were demonstrated. At the RNA level the overexpression of tumor-associated genes was shown. These observations laid the foundation for the development of assays for an early detection of cancer as well as for other clinical means.
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              About the possible origin and mechanism of circulating DNA apoptosis and active DNA release.

              M Stroun, J Lyautey, C Lederrey … (2001)
              In addition to cell lysis, apoptosis has been advanced as the origin of circulating DNA on the basis of several observations. Plasma or serum DNA often presents a ladder pattern reminiscent of that displayed by apoptotic cells when subjected to electrophoresis. However, the phenomenon of active release of DNA from cells might also be expected to result in a ladder pattern on electrophoresis. Non-dividing cells, such as lymphocytes, frog auricles and cultured cell lines including HL-60, spontaneously release a nucleoprotein complex within a homeostatic system in which newly synthesized DNA is preferentially released. In relation to DNA synthesis, the phenomenon of extracellular DNA in different culture conditions favors apoptosis or spontaneous active DNA release.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 6 September 2011
                Volume: 6
                Issue: 9
                Electronic Location Identifier: e23418
                Affiliations
                [1 ]SysDiag UMR3145 – CNRS, National Centre of the Scientific Research/BIO-RAD, Montpellier, France
                [2 ]U896 INSERM, National Institute of Health and Medical Research, University Montpellier1, IRCM, Institute of Oncological Research of Montpellier, Montpellier, France
                [3 ]CRLC, Regional Centre against Cancer, Val d'Aurelle-Paul Lamarque, Montpellier, France
                University of Hong Kong, Hong Kong
                Author notes

                Conceived and designed the experiments: F. Mouliere ART. Performed the experiments: F. Mouliere BR EAP CG. Analyzed the data: F. Mouliere BR EAP MDR MY F. Molina CG ART. Contributed reagents/materials/analysis tools: BR MY. Wrote the paper: F. Mouliere CG ART.

                Article
                Publisher ID: PONE-D-11-07649
                DOI: 10.1371/journal.pone.0023418
                PMC ID: 3167805
                PubMed ID: 21909401
                SO-VID: 8f1c211b-2150-4109-8209-73aad01726bf
                Copyright © Mouliere et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 5 May 2011
                Date accepted : 16 July 2011
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Nucleic Acids
                Subject: DNA
                Subject: Biophysics
                Subject: Nucleic Acids
                Subject: DNA
                Subject: Molecular Cell Biology
                Subject: Nucleic Acids
                Subject: DNA
                Subject: Cell Death
                Subject: Medicine
                Subject: Gastroenterology and Hepatology
                Subject: Gastrointestinal Cancers
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Cancer Detection and Diagnosis

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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