Sensitive tumour detection and classification using plasma cell-free DNA methylomes
Open accessAbstract
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.
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“it has recently become apparent that vertebrate specific chromatin complexes such as the HUSH complex can be major regulators of the LINE-1 family of retrotransposons 218,219 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [218]
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Self-citation
- Authors
- Shen, S. Y., Singhania, R., Fehringer, G., Chakravarthy, A., Roehrl, M. H. A., Chadwick, D., Zuzarte, P. C., Borgida, A., Wang, T. T., Li, T., Kis, O., Zhao, Z., Spreafico, A., Medina, T. D. S., Wang, Y., Roulois, D., Ettayebi, I., Chen, Z., Chow, S., Murphy, T., Arruda, A., O’Kane, G. M., Liu, J., Mansour, M., McPherson, J. D., O’Brien, C., Leighl, N., Bedard, P. L., Fleshner, N., Liu, G., Minden, M. D., Gallinger, S., Goldenberg, A., Pugh, T. J., Hoffman, M. M., Bratman, S. V., Hung, R. J., & De Carvalho, D. D.
- Affiliations
- University Health Network (CA)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Ontario Institute for Cancer Research (CA)
- University of Toronto (CA)
- UC Davis Comprehensive Cancer Center (US)
- Corresponding author
- Hung, Rayjean J.
- ORCID
- Shen, Shu Yi
- Singhania, Rajat
- Fehringer, Gordon
- Chakravarthy, Ankur
- Roehrl, Michael H. A.
- Zuzarte, Philip C.
- Borgida, Ayelet
- Li, Tiantian
- Zhao, Zhen
- Spreafico, Anna
- Medina, Tiago da Silva
- Roulois, David
- Ettayebi, Ilias
- Chen, Zhuo
- Chow, Signy
- Murphy, Tracy
- Arruda, Andrea
- Mansour, Mark
- McPherson, John D.
- Leighl, Natasha
- Bedard, Philippe L.
- Fleshner, Neil
- Liu, Geoffrey
- Minden, Mark D.
- Goldenberg, Anna
- Pugh, Trevor J.
- Hoffman, Michael M.
- Bratman, Scott V.
- Hung, Rayjean J.
- Venue
- Nature
- Published
- 2018-11
- Volume
- 563
- Issue
- 7732
- Pages
- 579-583
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2900771557
- Cited by
- 983
- References
- 38
- Citations by year
- 2026: 99 · 2025: 118 · 2024: 135 · 2023: 135 · 2022: 149 · 2021: 155 · 2020: 115 · 2019: 73 · 2018: 1 · 2017: 1 · 2013: 1
- FWCI
- 26.53
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- TSpace (University of Toronto) (submittedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Care Ontario
- Princess Margaret Cancer Foundation (950-231346)
- University of Toronto
- Canadian Institutes of Health Research (148430_1, 201512MSH-360794-228629, 148430, 201512MSH‐)
- Canadian Cancer Society Research Institute (703827, 020214)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Keywords
- circulating tumor DNA, cell-free DNA, DNA methylation, liquid biopsy, early-stage cancer detection, cancer classification, plasma biomarkers
- MeSH terms
- Cell-Free Nucleic Acids, Liquid Biopsy, Adenocarcinoma, Animals, DNA Mutational Analysis, DNA, Neoplasm, Female, Humans, Male, Neoplasm Transplantation, Neoplasms, Organ Specificity, Pancreatic Neoplasms, Biomarkers, Tumor, Colorectal Neoplasms, Mice, SCID, Mice, Inbred NOD, DNA Methylation, Epigenesis, Genetic, Cell Line, Tumor, Mice, Early Detection of Cancer, Heterografts
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