Genetic-epigenetic tissue mapping for plasma DNA: applications in prenatal testing, transplantation and oncology

  1. Wanxia Gai
  2. Ze Zhou
  3. Sean Agbor-Enoh
  4. Xiaodan Fan
  5. Sheng Lian
  6. Peiyong Jiang
  7. Suk Hang Cheng
  8. John Wong
  9. Stephen Lam Chan
  10. Moon Kyoo Jang
  11. Yanqin Yang
  12. Raymond H S Liang
  13. Wai Kong Chan
  14. Edmond S K Ma
  15. Tak Y Leung
  16. Rossa W K Chiu
  17. Hannah Valantine
  18. K C Allen Chan
  19. Y M Dennis Lo  Is a corresponding author
  1. The Chinese University of Hong Kong, Hong Kong
  2. Johns Hopkins School of Medicine, United States
  3. National Heart, Lung and Blood Institute, United States
  4. Hong Kong Sanatorium and Hospital, Hong Kong

Abstract

We developed Genetic-Epigenetic Tissue Mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung-transplant recipients, we showed that, at 72 hours after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring and cancer screening.

Data availability

Sequencing data have been deposited in EGA under the accession code EGAS00001004788.

The following data sets were generated

Article and author information

Author details

  1. Wanxia Gai

    Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
  2. Ze Zhou

    Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
  3. Sean Agbor-Enoh

    Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Xiaodan Fan

    Department of Statistics, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2744-9030
  5. Sheng Lian

    Statistics, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
  6. Peiyong Jiang

    Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    Peiyong Jiang, Holds equities in Grail.Serves as a director of KingMed Future.Received patent royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom.Filed a patent application (US15/214,998)..
  7. Suk Hang Cheng

    Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
  8. John Wong

    Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
  9. Stephen Lam Chan

    Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  10. Moon Kyoo Jang

    Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  11. Yanqin Yang

    Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  12. Raymond H S Liang

    Comprehensive Oncology Centre, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
    Competing interests
    No competing interests declared.
  13. Wai Kong Chan

    Pathology, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
    Competing interests
    No competing interests declared.
  14. Edmond S K Ma

    Pathology, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
    Competing interests
    No competing interests declared.
  15. Tak Y Leung

    Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    No competing interests declared.
  16. Rossa W K Chiu

    Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    Rossa W K Chiu, Holds equities in DRA, Take2 and Grail.Is a consultant to Grail and Illumina.Receives research funding from Grail.Receives royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom.Filed a patent application (US15/214,998)..
  17. Hannah Valantine

    Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  18. K C Allen Chan

    Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
    Competing interests
    K C Allen Chan, Holds equities in DRA, Take2 and Grail.Is a consultant to and receives research funding from Grail.Receives royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom.Filed a patent application (US15/214,998)..
  19. Y M Dennis Lo

    Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    For correspondence
    loym@cuhk.edu.hk
    Competing interests
    Y M Dennis Lo, Reviewing editor, eLife.Holds equities in DRA, Take2 and Grail.Is a consultant, scientific cofounder and scientific advisory board member of Grail.Received patent royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom.Had filed a patent application (US15/214,998)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8746-0293

Funding

Research Grants Council, University Grants Committee (Theme-based research scheme T12-403/15-N)

  • Rossa W K Chiu
  • K C Allen Chan
  • Y M Dennis Lo

Research Grants Council, University Grants Committee (Theme-based research scheme T12-401/16-W)

  • Rossa W K Chiu
  • K C Allen Chan
  • Y M Dennis Lo

Chinese University of Hong Kong (VCF2014021)

  • Rossa W K Chiu
  • K C Allen Chan
  • Y M Dennis Lo

Grail (Collaborative research agreement)

  • Rossa W K Chiu
  • K C Allen Chan
  • Y M Dennis Lo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The project was approved by the Joint Chinese University of Hong Kong-Hospital Authority New Territories East Cluster Clinical Research Ethics Committee (approval reference number 2011.204). All participants provided written informed consent.

Reviewing Editor

  1. Tony Yuen

Publication history

  1. Received: October 26, 2020
  2. Accepted: March 10, 2021
  3. Accepted Manuscript published: March 23, 2021 (version 1)
  4. Version of Record published: March 26, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Wanxia Gai
  2. Ze Zhou
  3. Sean Agbor-Enoh
  4. Xiaodan Fan
  5. Sheng Lian
  6. Peiyong Jiang
  7. Suk Hang Cheng
  8. John Wong
  9. Stephen Lam Chan
  10. Moon Kyoo Jang
  11. Yanqin Yang
  12. Raymond H S Liang
  13. Wai Kong Chan
  14. Edmond S K Ma
  15. Tak Y Leung
  16. Rossa W K Chiu
  17. Hannah Valantine
  18. K C Allen Chan
  19. Y M Dennis Lo
(2021)
Genetic-epigenetic tissue mapping for plasma DNA: applications in prenatal testing, transplantation and oncology
eLife 10:e64356.
https://doi.org/10.7554/eLife.64356

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