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

Shu Yi Shen, Rajat Singhania, Gordon Fehringer, Ankur Chakravarthy, Michael H. A. Roehrl, Dianne Chadwick, Philip C. Zuzarte, Ayelet Borgida, Ting Ting Wang, Tiantian Li, Olena Kis, Zhen Zhao, Anna Spreafico, Tiago da Silva Medina, Yadon Wang, David Roulois, Ilias Ettayebi, Zhuo Chen, Signy Chow, Tracy Murphy, Andrea Arruda, Grainne M. O’Kane, Jessica Liu, Mark Mansour, John D. McPherson, Catherine O’Brien, Natasha Leighl, Philippe L. Bedard, Neil Fleshner, Geoffrey Liu, Mark D. Minden, Steven Gallinger, Anna Goldenberg, Trevor J. Pugh, Michael M. Hoffman, Scott V. Bratman, Rayjean J. Hung () and Daniel D. Carvalho ()
Additional contact information
Shu Yi Shen: University Health Network
Rajat Singhania: University Health Network
Gordon Fehringer: Sinai Health System
Ankur Chakravarthy: University Health Network
Michael H. A. Roehrl: University Health Network
Dianne Chadwick: University Health Network
Philip C. Zuzarte: Ontario Institute for Cancer Research
Ayelet Borgida: Sinai Health System
Ting Ting Wang: University Health Network
Tiantian Li: University Health Network
Olena Kis: University Health Network
Zhen Zhao: University Health Network
Anna Spreafico: University Health Network
Tiago da Silva Medina: University Health Network
Yadon Wang: University Health Network
David Roulois: University Health Network
Ilias Ettayebi: University Health Network
Zhuo Chen: University Health Network
Signy Chow: University Health Network
Tracy Murphy: University Health Network
Andrea Arruda: University Health Network
Grainne M. O’Kane: University Health Network
Jessica Liu: University of Toronto
Mark Mansour: University of Toronto
John D. McPherson: UC Davis Comprehensive Cancer Center
Catherine O’Brien: University Health Network
Natasha Leighl: University Health Network
Philippe L. Bedard: University Health Network
Neil Fleshner: University Health Network
Geoffrey Liu: University Health Network
Mark D. Minden: University Health Network
Steven Gallinger: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Anna Goldenberg: University of Toronto
Trevor J. Pugh: University Health Network
Michael M. Hoffman: University Health Network
Scott V. Bratman: University Health Network
Rayjean J. Hung: Sinai Health System
Daniel D. Carvalho: University Health Network

Nature, 2018, vol. 563, issue 7732, 579-583

Abstract: 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.

Keywords: Differentially Methylated Regions (DMRs); Reduced Representation Bisulfite Sequencing (RRBS); Differentially Methylated CpGs (DMCs); Plasma cfDNA; Unique Molecular Identifiers (UMIs) (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0703-0

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