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

Stephen Cristiano, Alessandro Leal, Jillian Phallen, Jacob Fiksel, Vilmos Adleff, Daniel C. Bruhm, Sarah Østrup Jensen, Jamie E. Medina, Carolyn Hruban, James R. White, Doreen N. Palsgrove, Noushin Niknafs, Valsamo Anagnostou, Patrick Forde, Jarushka Naidoo, Kristen Marrone, Julie Brahmer, Brian D. Woodward, Hatim Husain, Karlijn L. Rooijen, Mai-Britt Worm Ørntoft, Anders Husted Madsen, Cornelis J. H. Velde, Marcel Verheij, Annemieke Cats, Cornelis J. A. Punt, Geraldine R. Vink, Nicole C. T. Grieken, Miriam Koopman, Remond J. A. Fijneman, Julia S. Johansen, Hans Jørgen Nielsen, Gerrit A. Meijer, Claus Lindbjerg Andersen, Robert B. Scharpf () and Victor E. Velculescu ()
Additional contact information
Stephen Cristiano: Johns Hopkins University School of Medicine
Alessandro Leal: Johns Hopkins University School of Medicine
Jillian Phallen: Johns Hopkins University School of Medicine
Jacob Fiksel: Johns Hopkins University School of Medicine
Vilmos Adleff: Johns Hopkins University School of Medicine
Daniel C. Bruhm: Johns Hopkins University School of Medicine
Sarah Østrup Jensen: Aarhus University Hospital
Jamie E. Medina: Johns Hopkins University School of Medicine
Carolyn Hruban: Johns Hopkins University School of Medicine
James R. White: Johns Hopkins University School of Medicine
Doreen N. Palsgrove: Johns Hopkins University School of Medicine
Noushin Niknafs: Johns Hopkins University School of Medicine
Valsamo Anagnostou: Johns Hopkins University School of Medicine
Patrick Forde: Johns Hopkins University School of Medicine
Jarushka Naidoo: Johns Hopkins University School of Medicine
Kristen Marrone: Johns Hopkins University School of Medicine
Julie Brahmer: Johns Hopkins University School of Medicine
Brian D. Woodward: University of California, San Diego
Hatim Husain: University of California, San Diego
Karlijn L. Rooijen: University Medical Center, Utrecht University
Mai-Britt Worm Ørntoft: Aarhus University Hospital
Anders Husted Madsen: Herning Regional Hospital
Cornelis J. H. Velde: Leiden University Medical Center
Marcel Verheij: The Netherlands Cancer Institute
Annemieke Cats: The Netherlands Cancer Institute
Cornelis J. A. Punt: Academic Medical Center, University of Amsterdam
Geraldine R. Vink: University Medical Center, Utrecht University
Nicole C. T. Grieken: VU University Medical Center
Miriam Koopman: University Medical Center, Utrecht University
Remond J. A. Fijneman: The Netherlands Cancer Institute
Julia S. Johansen: Copenhagen University Hospital
Hans Jørgen Nielsen: Department of Surgical Gastroenterology 360, Hvidovre Hospital
Gerrit A. Meijer: The Netherlands Cancer Institute
Claus Lindbjerg Andersen: Aarhus University Hospital
Robert B. Scharpf: Johns Hopkins University School of Medicine
Victor E. Velculescu: Johns Hopkins University School of Medicine

Nature, 2019, vol. 570, issue 7761, 385-389

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1272-6

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