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Nature. 2018 Nov;563(7732):579-583. doi: 10.1038/s41586-018-0703-0. Epub 2018 Nov 14.

Sensitive tumour detection and classification using plasma cell-free DNA methylomes.

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
2
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
3
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
5
Genome Technologies, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
6
UMR_S 1236, Univ Rennes 1, Inserm, Etablissement Fran├žais du sang Bretagne, Rennes, France.
7
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.
8
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
9
Fred Litwin Centre for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
10
Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
11
Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
12
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. rayjean.hung@lunenfeld.ca.
13
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. rayjean.hung@lunenfeld.ca.
14
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca.
15
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca.

Abstract

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.

PMID:
30429608
DOI:
10.1038/s41586-018-0703-0
[Indexed for MEDLINE]

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