Genome-wide cell-free DNA fragmentation in patients with cancer

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperLetterResearchpeer-review

  • Stephen Cristiano, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
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  • Alessandro Leal, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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  • Jillian Phallen, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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  • Jacob Fiksel, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
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  • Vilmos Adleff, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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  • Daniel C Bruhm, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Sarah Østrup Jensen
  • Jamie E Medina, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Carolyn Hruban, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • James R White, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Doreen N Palsgrove, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Noushin Niknafs, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Valsamo Anagnostou, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Patrick Forde, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Jarushka Naidoo, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Kristen Marrone, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • ,
  • Julie Brahmer, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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  • Hatim Husain, Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
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  • Karlijn L van Rooijen, Department of Medical Oncology, University Medical Center, Utrecht University, Utrecht, The Netherlands, Netherlands
  • Mai-Britt Worm Ørntoft
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  • Anders Husted Madsen
  • Cornelis J H van de Velde, Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
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  • Marcel Verheij, Department of Radiation Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
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  • Annemieke Cats, Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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  • Cornelis J A Punt, Department of Radiation Oncology Academic Medical Center, University of Amsterdam, The Netherlands.
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  • Geraldine R Vink, Department of Medical Oncology, University Medical Center, Utrecht University, Utrecht, The Netherlands
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  • Nicole C T van Grieken, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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  • Miriam Koopman, Department of Medical Oncology, University Medical Center, Utrecht University, Utrecht, The Netherlands, Netherlands
  • Remond J A Fijneman, Department of pathology, Antoni van Leeuwenhoek hospital/the Netherlands Cancer Institute, Amsterdam, The Netherlands. p.snaebjornsson@nki.nl.
  • ,
  • Julia S Johansen, Department of Oncology, Herlev Hospital, University of Copenhagen
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  • Hans Jørgen Nielsen, Department of Surgical Gastroenterology 360, Hvidovre Hospital, Hvidovre, Denmark., Denmark
  • Gerrit A Meijer, Department of pathology, Antoni van Leeuwenhoek hospital/the Netherlands Cancer Institute, Amsterdam, The Netherlands. p.snaebjornsson@nki.nl.
  • ,
  • Claus Lindbjerg Andersen
  • Robert B Scharpf, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. rscharpf@jhu.edu.
  • ,
  • Victor E Velculescu, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. velculescu@jhmi.edu.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.

Original languageEnglish
JournalNature
Volume570
Issue7761
Pages (from-to)385-389
Number of pages5
ISSN0028-0836
DOIs
Publication statusPublished - Jun 2019

    Research areas

  • ABERRATIONS, CIRCULATING DNA, INTEGRITY, PLASMA DNA

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