Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32995-6
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Funding
- National Cancer Institute [U01CA230705, R01CA246329, U01CA237711, R43CA246941, R01CA210360, U01CA214182, R01CA253651, R01CA246304]
- National Science Foundation Graduate Research Fellowship [DGE-1418060]
- National Institute of Health [UM1HG011593, R01CA255727]
- Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Cancer Research Grant [SU2C-AACR-DT23-17]
- American Association for Cancer Research, the scientific partner of SU2C
- Department of Veteran Affairs
- UCLA DGSOM
- UCLA Health
- Department of Radiological Sciences, David Geffen School of Medicine at UCLA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA
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Early cancer detection using cell-free DNA faces challenges of low tumor DNA fraction, molecular heterogeneity, and limited sample sizes. In this study, the authors developed a cost-effective method called cfMethyl-Seq to profile the methylome of cell-free DNA and detect and locate cancer. The approach achieved high sensitivity and accuracy for detecting and identifying the tissue-of-origin of various cancer types.
Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow. Early cancer detection by cell-free DNA (cfDNA) is challenged by the low amount of tumour DNA in cfDNA, tumour heterogeneity and the small patient cohorts. Here, the authors develop a method, cfMethyl-Seq, for cost-effective methylome profiling of cfDNA and for detecting and locating cancer.
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