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

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence 1 . 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 cance...

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Published in:	Nature (London) Vol. 563; no. 7732; pp. 579 - 583
Main Authors:	Shen, Shu Yi, Singhania, Rajat, Fehringer, Gordon, Chakravarthy, Ankur, Roehrl, Michael H. A., Chadwick, Dianne, Zuzarte, Philip C., Borgida, Ayelet, Wang, Ting Ting, Li, Tiantian, Kis, Olena, Zhao, Zhen, Spreafico, Anna, Medina, Tiago da Silva, Wang, Yadon, Roulois, David, Ettayebi, Ilias, Chen, Zhuo, Chow, Signy, Murphy, Tracy, Arruda, Andrea, O’Kane, Grainne M., Liu, Jessica, Mansour, Mark, McPherson, John D., O’Brien, Catherine, Leighl, Natasha, Bedard, Philippe L., Fleshner, Neil, Liu, Geoffrey, Minden, Mark D., Gallinger, Steven, Goldenberg, Anna, Pugh, Trevor J., Hoffman, Michael M., Bratman, Scott V., Hung, Rayjean J., De Carvalho, Daniel D.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-11-2018 Nature Publishing Group
Subjects:	45/23 631/1647/2210/2213 631/67/69 Adenocarcinoma - blood Adenocarcinoma - genetics Animals Biochemistry, Molecular Biology Bioinformatics Biological markers Biomarkers Biomarkers, Tumor - genetics Cancer Cancer diagnosis Cell Line, Tumor Cell-Free Nucleic Acids - blood Cell-Free Nucleic Acids - metabolism Change detection Classification Colorectal Neoplasms - blood Colorectal Neoplasms - genetics Deoxyribonucleic acid DNA DNA Methylation DNA Mutational Analysis DNA sequencing DNA, Neoplasm - blood DNA, Neoplasm - metabolism Early Detection of Cancer - methods Epigenesis, Genetic Epigenetic inheritance Epigenetics Female Generalized linear models Genetic aspects Genetic research Genomes Genomics Heterografts Humanities and Social Sciences Humans Identification and classification Immunoprecipitation Interception Letter Life Sciences Liquid Biopsy Male Medical screening Methods Methylation Mice Mice, Inbred NOD Mice, SCID multidisciplinary Multiple myeloma Mutation Neoplasm Transplantation Neoplasms - blood Neoplasms - classification Neoplasms - genetics Organ Specificity Pancreatic cancer Pancreatic Neoplasms - blood Pancreatic Neoplasms - genetics Patients Science Science (multidisciplinary) Testing Tumors Differentially Methylated Regions (DMRs) Differentially Methylated CpGs (DMCs) Reduced Representation Bisulfite Sequencing (RRBS) Plasma cfDNA Unique Molecular Identifiers (UMIs)
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Summary:	The use of liquid biopsies for cancer detection and management is rapidly gaining prominence 1 . 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 mutations 2 – 5 . By contrast, large-scale epigenetic alterations—which are tissue- and cancer-type specific—are not similarly constrained 6 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-018-0703-0