Journal
NATURE BIOTECHNOLOGY
Volume 41, Issue 2, Pages 212-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41587-022-01447-3
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This study developed a single-molecule imaging technique that can accurately and sensitively detect colorectal cancer in cell-free nucleosomes. By analyzing the epigenetics, DNA methylation, and cancer-specific protein biomarkers of plasma-isolated nucleosomes, the system allows for high-resolution detection of histone modifications and provides quantitative data on plasma proteins. The analysis showed high accuracy and sensitivity in detecting cancer, even at early stages, and could determine the tissue origin of tumors.
Single-molecule imaging of cell-free nucleosomes detects colorectal cancer with high accuracy and sensitivity. The analysis of cell-free DNA (cfDNA) in plasma provides information on pathological processes in the body. Blood cfDNA is in the form of nucleosomes, which maintain their tissue- and cancer-specific epigenetic state. We developed a single-molecule multiparametric assay to comprehensively profile the epigenetics of plasma-isolated nucleosomes (EPINUC), DNA methylation and cancer-specific protein biomarkers. Our system allows for high-resolution detection of six active and repressive histone modifications and their ratios and combinatorial patterns on millions of individual nucleosomes by single-molecule imaging. In addition, our system provides sensitive and quantitative data on plasma proteins, including detection of non-secreted tumor-specific proteins, such as mutant p53. EPINUC analysis of a cohort of 63 colorectal cancer, 10 pancreatic cancer and 33 healthy plasma samples detected cancer with high accuracy and sensitivity, even at early stages. Finally, combining EPINUC with direct single-molecule DNA sequencing revealed the tissue of origin of colorectal, pancreatic, lung and breast tumors. EPINUC provides multilayered information of potential clinical relevance from limited (<1 ml) liquid biopsy material.
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