Sensitive tumour detection and classification using plasma cell-free DNA methylomes. (22nd November 2018)

• Record Type: Journal Article
• Authors: Shen, Shu; Singhania, Rajat; Fehringer, Gordon; Chakravarthy, Ankur; Roehrl, Michael; Chadwick, Dianne; Zuzarte, Philip; Borgida, Ayelet; Wang, Ting; Li, Tiantian; Kis, Olena; Zhao, Zhen; Spreafico, Anna; Medina, Tiago; Wang, Yadon; Roulois, David; Ettayebi, Ilias; Chen, Zhuo; Chow, Signy; Murphy, Tracy; Arruda, Andrea; O'Kane, Grainne; Liu, Jessica; Mansour, Mark; McPherson, John; O'Brien, Catherine; Leighl, Natasha; Bedard, Philippe; Fleshner, Neil; Liu, Geoffrey; Minden, Mark; Gallinger, Steven; Goldenberg, Anna; Pugh, Trevor; Hoffman, Michael; Bratman, Scott; Hung, Rayjean; Carvalho, Daniel;
• Is Part Of: Nature. Volume 563:Number 7732(2018)
• Page Start: 579
• Page End: 583
• Publication Date: 2018-11-22
• Subjects: Science -- Periodicals; 505
• DOI: 10.1038/s41586-018-0703-0
• Languages: English
• ISSNs: 0028-0836

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. An immunoprecipitation-based protocol is developed to analyse DNA methylation in small quantities of circulating cell-free DNA, and can detect and classify cancers in plasma samples from several tumour types.