Format

Send to

Choose Destination
Nature. 2019 Jun;570(7761):385-389. doi: 10.1038/s41586-019-1272-6. Epub 2019 May 29.

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

Author information

1
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
3
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
4
Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
5
Department of Medical Oncology, University Medical Center, Utrecht University, Utrecht, The Netherlands.
6
Department of Surgery, Herning Regional Hospital, Herning, Denmark.
7
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
8
Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
9
Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
10
Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
11
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
12
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
13
Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
14
Department of Surgical Gastroenterology 360, Hvidovre Hospital, Hvidovre, Denmark.
15
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rscharpf@jhu.edu.
16
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. rscharpf@jhu.edu.
17
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. velculescu@jhmi.edu.

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.

PMID:
31142840
DOI:
10.1038/s41586-019-1272-6

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center