title: Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments.
abstract: Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Peiyong
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: K C Allen
authors.initials: KC
authors.lastname: Chan
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Yvonne K Y
authors.initials: YK
authors.lastname: Cheng
authors.affiliation: Comprehensive Oncology Centre, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China;
authors.forename: Raymond H S
authors.initials: RH
authors.lastname: Liang
authors.affiliation: Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China;
authors.forename: Wai-kong
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China;
authors.forename: Edmond S K
authors.initials: ES
authors.lastname: Ma
authors.affiliation: Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Suk Hang
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Rebecca W Y
authors.initials: RW
authors.lastname: Chan
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Yu K
authors.initials: YK
authors.lastname: Tong
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China;
authors.forename: Raymond S M
authors.initials: RS
authors.lastname: Wong
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: David S C
authors.initials: DS
authors.lastname: Hui
authors.affiliation: Obstetrics and Gynaecology Centre, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China.
authors.forename: Tse Ngong
authors.initials: TN
authors.lastname: Leung
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Tak Y
authors.initials: TY
authors.lastname: Leung
authors.affiliation: State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Rossa W K
authors.initials: RW
authors.lastname: Chiu
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; loym@cuhk.edu.hk.
authors.forename: Yuk Ming Dennis
authors.initials: YM
authors.lastname: Lo
mesh_terms: D000328:Adult; D000465:Algorithms; D001402:B-Lymphocytes / Q000378:metabolism; D016026:Bone Marrow Transplantation; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005333:Fetus / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000235:genetics*; D016031:Liver Transplantation; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D017422:Sequence Analysis, DNA / Q000379:methods*; D013601:T-Lymphocytes / Q000378:metabolism; D016378:Tissue Transplantation
chemical_list: D004247:DNA
keywords: circulating tumor DNA; epigenetics; liquid biopsy; noninvasive prenatal testing; transplantation monitoring