TY - JOUR
T1 - Genome-wide cell-free DNA fragmentation in patients with cancer
AU - Cristiano, Stephen
AU - Leal, Alessandro
AU - Phallen, Jillian
AU - Fiksel, Jacob
AU - Adleff, Vilmos
AU - Bruhm, Daniel C.
AU - Jensen, Sarah Østrup
AU - Medina, Jamie E.
AU - Hruban, Carolyn
AU - White, James R.
AU - Palsgrove, Doreen N.
AU - Niknafs, Noushin
AU - Anagnostou, Valsamo
AU - Forde, Patrick
AU - Naidoo, Jarushka
AU - Marrone, Kristen
AU - Brahmer, Julie
AU - Woodward, Brian D.
AU - Husain, Hatim
AU - van Rooijen, Karlijn L.
AU - Ørntoft, Mai Britt Worm
AU - Madsen, Anders Husted
AU - van de Velde, Cornelis J.H.
AU - Verheij, Marcel
AU - Cats, Annemieke
AU - Punt, Cornelis J.A.
AU - Vink, Geraldine R.
AU - van Grieken, Nicole C.T.
AU - Koopman, Miriam
AU - Fijneman, Remond J.A.
AU - Johansen, Julia S.
AU - Nielsen, Hans Jørgen
AU - Meijer, Gerrit A.
AU - Andersen, Claus Lindbjerg
AU - Scharpf, Robert B.
AU - Velculescu, Victor E.
N1 - Funding Information:
Acknowledgements We thank members of our laboratories for critical review of the manuscript. This work was supported, in part, by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Stand Up to Cancer– Dutch Cancer Society International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415), the Commonwealth Foundation, the Cigarette Restitution Fund, the Burroughs Wellcome Fund and the Maryland Genetics, Epidemiology and Medicine Training Program, the AACR-Janssen Cancer Interception Research Fellowship, the Mark Foundation for Cancer Research, US NIH (grants CA121113, CA006973, and CA180950), the Danish Council for Independent Research (11-105240), the Danish Council for Strategic Research (1309-00006B), the Novo Nordisk Foundation (NNF14OC0012747 and NNF17OC0025052), and the Danish Cancer Society (R133-A8520-00-S41 and R146-A9466-16-S2). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/6/20
Y1 - 2019/6/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066798739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066798739&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1272-6
DO - 10.1038/s41586-019-1272-6
M3 - Article
C2 - 31142840
AN - SCOPUS:85066798739
SN - 0028-0836
VL - 570
SP - 385
EP - 389
JO - Nature
JF - Nature
IS - 7761
ER -