Liquid biopsy reveals collateral tissue damage in cancer

Asael Lubotzky, Hai Zemmour, Daniel Neiman, Marc Gotkine, Netanel Loyfer, Sheina Piyanzin, Bracha Lea Ochana, Roni Lehmann-Werman, Daniel Cohen, Joshua Moss, Judith Magenheim, Maureen F. Loftus, Lauren Brais, Kimmie Ng, Raul Mostoslavsky, Brian M. Wolpin, Aviad Zick, Myriam Maoz, Albert Grinshpun, Anatoli KustanovichChen Makranz, Jonathan E. Cohen, Tamar Peretz, Ayala Hubert, Mark Temper, Azzam Salah, Shani Avniel-Polak, Simona Grozinsky-Glasberg, Kirsty L. Spalding, Ariel Rokach, Tommy Kaplan, Benjamin Glaser, Ruth Shemer, Yuval Dor

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissuespecific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type-specific cfDNA methylation markers enable the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.

Original languageAmerican English
Article numbere153559
JournalJCI insight
Issue number2
StatePublished - Jan 2022

Bibliographical note

Funding Information:
This work was supported by grants from Grail, The Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, the Alex U. Soyka pancreatic cancer fund, the Israel Science Foundation, the Waldholtz/Pakula family, the Robert and Marilyn Sternberg Charitable Foundation, the Grant for Multiple Sclerosis Innovation from Merck (to YD), the Israel Cancer Research Fund (to AZ), and the Israel Cancer Research Fund (to AL). YD holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. Sample collection and investigators at Dana-Farber Cancer Institute were supported by the Hale Family Center for Pancreatic Cancer Research, Lustgarten Foundation Dedicated Pancreatic Cancer Research Laboratory program, and NIH grant U01 CA210171. AG was supported by the Ministry of Science and Technology, Israel (Personalized Medicine Grant 2017-2020).

Publisher Copyright:
© 2022, Lubotzky et al.


  • Cell Biology
  • Epigenetics
  • Molecular diagnosis
  • Oncology
  • Cell-Free Nucleic Acids/analysis
  • Humans
  • Brain Neoplasms/genetics
  • Pancreatic Neoplasms/complications
  • Liver Neoplasms/genetics
  • Early Detection of Cancer/methods
  • DNA Methylation
  • Neoplasm Metastasis/genetics
  • Liquid Biopsy/methods
  • Hepatocytes/metabolism
  • Biomarkers, Tumor/analysis


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