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 Kustanovich; Chen 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

doi:10.1172/jci.insight.153559

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 journal › Article › peer-review

18 Scopus citations

Abstract

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 language	American English
Article number	e153559
Journal	JCI insight
Volume	7
Issue number	2
DOIs	https://doi.org/10.1172/jci.insight.153559
State	Published - 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.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/jci.insight.153559

Cite this

Lubotzky, A., Zemmour, H., Neiman, D., Gotkine, M., Loyfer, N., Piyanzin, S., Ochana, B. L., Lehmann-Werman, R., Cohen, D., Moss, J., Magenheim, J., Loftus, M. F., Brais, L., Ng, K., Mostoslavsky, R., Wolpin, B. M., Zick, A., Maoz, M., Grinshpun, A., ... Dor, Y. (2022). Liquid biopsy reveals collateral tissue damage in cancer. JCI insight, 7(2), Article e153559. https://doi.org/10.1172/jci.insight.153559

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title = "Liquid biopsy reveals collateral tissue damage in cancer",

abstract = "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.",

keywords = "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",

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

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: {\textcopyright} 2022, Lubotzky et al.",

year = "2022",

month = jan,

doi = "10.1172/jci.insight.153559",

language = "American English",

volume = "7",

journal = "JCI insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "2",

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Lubotzky, A, Zemmour, H, Neiman, D, Gotkine, M, Loyfer, N, Piyanzin, S, Ochana, BL, Lehmann-Werman, R, Cohen, D, Moss, J, Magenheim, J, Loftus, MF, Brais, L, Ng, K, Mostoslavsky, R, Wolpin, BM, Zick, A, Maoz, M, Grinshpun, A, Kustanovich, A, Makranz, C, Cohen, JE, Peretz, T, Hubert, A, Temper, M, Salah, A, Avniel-Polak, S, Grozinsky-Glasberg, S, Spalding, KL, Rokach, A, Kaplan, T, Glaser, B, Shemer, R & Dor, Y 2022, 'Liquid biopsy reveals collateral tissue damage in cancer', JCI insight, vol. 7, no. 2, e153559. https://doi.org/10.1172/jci.insight.153559

TY - JOUR

T1 - Liquid biopsy reveals collateral tissue damage in cancer

AU - Lubotzky, Asael

AU - Zemmour, Hai

AU - Neiman, Daniel

AU - Gotkine, Marc

AU - Loyfer, Netanel

AU - Piyanzin, Sheina

AU - Ochana, Bracha Lea

AU - Lehmann-Werman, Roni

AU - Cohen, Daniel

AU - Moss, Joshua

AU - Magenheim, Judith

AU - Loftus, Maureen F.

AU - Brais, Lauren

AU - Ng, Kimmie

AU - Mostoslavsky, Raul

AU - Wolpin, Brian M.

AU - Zick, Aviad

AU - Maoz, Myriam

AU - Grinshpun, Albert

AU - Kustanovich, Anatoli

AU - Makranz, Chen

AU - Cohen, Jonathan E.

AU - Peretz, Tamar

AU - Hubert, Ayala

AU - Temper, Mark

AU - Salah, Azzam

AU - Avniel-Polak, Shani

AU - Grozinsky-Glasberg, Simona

AU - Spalding, Kirsty L.

AU - Rokach, Ariel

AU - Kaplan, Tommy

AU - Glaser, Benjamin

AU - Shemer, Ruth

AU - Dor, Yuval

N1 - 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.

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

KW - Cell Biology

KW - Epigenetics

KW - Molecular diagnosis

KW - Oncology

KW - Cell-Free Nucleic Acids/analysis

KW - Humans

KW - Brain Neoplasms/genetics

KW - Pancreatic Neoplasms/complications

KW - Liver Neoplasms/genetics

KW - Early Detection of Cancer/methods

KW - DNA Methylation

KW - Neoplasm Metastasis/genetics

KW - Liquid Biopsy/methods

KW - Hepatocytes/metabolism

KW - Biomarkers, Tumor/analysis

UR - http://www.scopus.com/inward/record.url?scp=85123904525&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.153559

DO - 10.1172/jci.insight.153559

M3 - Article

C2 - 35076021

AN - SCOPUS:85123904525

SN - 2379-3708

VL - 7

JO - JCI insight

JF - JCI insight

IS - 2

M1 - e153559

ER -

Liquid biopsy reveals collateral tissue damage in cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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