Multiplexed, single-molecule, epigenetic analysis of plasma-isolated nucleosomes for cancer diagnostics

Vadim Fedyuk, Nir Erez, Noa Furth, Olga Beresh, Ekaterina Andreishcheva, Abhijeet Shinde, Daniel Jones, Barak Bar Zakai, Yael Mavor, Tamar Peretz, Ayala Hubert, Jonathan E. Cohen, Azzam Salah, Mark Temper, Albert Grinshpun, Myriam Maoz, Aviad Zick, Guy Ron, Efrat Shema

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalNature Biotechnology
DOIs
StateAccepted/In press - 2022
Externally publishedYes

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