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Departments of
1
Chemical Pathology and
2
Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR.
aAddress correspondence to this author at: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR. Fax 852-2194-6171; e-mail loym{at}cuhk.edu.hk.
Background: Despite current interest in the biology and diagnostic applications of cell-free DNA in plasma and serum, the cellular origin of this DNA is poorly understood. We used a sex-mismatched bone marrow transplantation model to study the relative contribution of hematopoietic and nonhematopoietic cells to circulating DNA.
Methods: We studied 22 sex-mismatched bone marrow transplantation patients. Paired buffy coat and plasma samples were obtained from all 22 patients. Matching serum samples were also obtained from seven of them. Plasma DNA, serum DNA, and buffy coat were quantified by real-time PCR of the SRY and ß-globin gene DNA. To investigate the effects of blood drawing and other preanalytical variables on plasma DNA concentrations, blood samples were also collected from 14 individuals who had not received transplants. The effects of blood sampling by syringe and needle, centrifugation, and time delay in blood processing were studied.
Results: The median percentage of Y-chromosome DNA in the plasma in female patients receiving bone marrow from male donors (59.5%) differed significantly (P <0.001) from that in the male patients receiving bone marrow from female donors (6.9%). This indicated that plasma DNA in the bone marrow transplantation recipients was predominantly of donor origin. Compared with paired plasma samples, serum samples had a median 14-fold higher DNA concentration, with the additional DNA being of donor origin. Control experiments indicated that none of the three tested preanalytical variables contributed to a significant change in cell-free DNA concentration.
Conclusions: After bone marrow transplantation, the DNA in plasma and serum is predominantly hematopoietic in origin. Apart from the biological implications of this observation, this finding suggests that plasma and serum can be used as alternative materials for the study of postbone marrow transplantation chimerism.
The following articles in journals at HighWire Press have cited this article:
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  E C W Hung, R W K Chiu, and Y M D Lo Detection of circulating fetal nucleic acids: a review of methods and applications J. Clin. Pathol., April 1, 2009; 62(4): 308 - 313. [Abstract] [Full Text] [PDF]
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 E. C.W. Hung, T. K.F. Shing, S. S.C. Chim, P. C. Yeung, R. W.Y. Chan, K. W. Chik, V. Lee, N. B.Y. Tsui, C.-K. Li, C. S.C. Wong, et al. Presence of Donor-Derived DNA and Cells in the Urine of Sex-Mismatched Hematopoietic Stem Cell Transplant Recipients: Implication for the Transrenal Hypothesis Clin. Chem., April 1, 2009; 55(4): 715 - 722. [Abstract] [Full Text] [PDF]
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J. Beck, H. B. Urnovitz, J. Riggert, M. Clerici, and E. Schutz Profile of the Circulating DNA in Apparently Healthy Individuals Clin. Chem., April 1, 2009; 55(4): 730 - 738. [Abstract] [Full Text] [PDF]
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S. R. Umansky From Transrenal DNA to Stem Cell Differentiation: An Unexpected Twist Clin. Chem., April 1, 2009; 55(4): 602 - 604. [Full Text] [PDF]
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K. Saukkonen, P. Lakkisto, V. Pettila, M. Varpula, S. Karlsson, E. Ruokonen, K. Pulkki, and for the Finnsepsis Study Group Cell-Free Plasma DNA as a Predictor of Outcome in Severe Sepsis and Septic Shock Clin. Chem., June 1, 2008; 54(6): 1000 - 1007. [Abstract] [Full Text] [PDF]
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S. S.C. Chim, S. Jin, T. Y.H. Lee, F. M.F. Lun, W. S. Lee, L. Y.S. Chan, Y. Jin, N. Yang, Y. K. Tong, T. Y. Leung, et al. Systematic Search for Placental DNA-Methylation Markers on Chromosome 21: Toward a Maternal Plasma-Based Epigenetic Test for Fetal Trisomy 21 Clin. Chem., March 1, 2008; 54(3): 500 - 511. [Abstract] [Full Text] [PDF]
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Y. M. Dennis Lo and R. W. K. Chiu Noninvasive Prenatal Diagnosis of Fetal Chromosomal Aneuploidies by Maternal Plasma Nucleic Acid Analysis Clin. Chem., March 1, 2008; 54(3): 461 - 466. [Abstract] [Full Text] [PDF]
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S. S.C. Chim, T. K.F. Shing, E. C.W. Hung, T.-y. Leung, T.-k. Lau, R. W.K. Chiu, and Y.M. Dennis Lo Detection and Characterization of Placental MicroRNAs in Maternal Plasma Clin. Chem., March 1, 2008; 54(3): 482 - 490. [Abstract] [Full Text] [PDF]
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 P. J. Bastian, G. S. Palapattu, S. Yegnasubramanian, X. Lin, C. G. Rogers, L. A. Mangold, B. Trock, M. Eisenberger, A. W. Partin, and W. G. Nelson Prognostic Value of Preoperative Serum Cell-Free Circulating DNA in Men with Prostate Cancer Undergoing Radical Prostatectomy Clin. Cancer Res., September 15, 2007; 13(18): 5361 - 5367. [Abstract] [Full Text] [PDF]
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 R. W.K. Chiu, S. S.C. Chim, I. H.N. Wong, C. S.C. Wong, W.-S. Lee, K. F. To, J. H.M. Tong, R. K.C. Yuen, A. S.W. Shum, J. K.C. Chan, et al. Hypermethylation of RASSF1A in Human and Rhesus Placentas Am. J. Pathol., March 1, 2007; 170(3): 941 - 950. [Abstract] [Full Text] [PDF]
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D. W. Bianchi Will Epigenetic Allelic Ratio Analysis Turn Prenatal Diagnosis of Trisomy 18 on Its EAR? Clin. Chem., December 1, 2006; 52(12): 2182 - 2183. [Full Text] [PDF]
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Y. K. Tong, C. Ding, R. W.K. Chiu, A. Gerovassili, S. S.C. Chim, T. Y. Leung, T. N. Leung, T. K. Lau, K. H. Nicolaides, and Y.M. D. Lo Noninvasive Prenatal Detection of Fetal Trisomy 18 by Epigenetic Allelic Ratio Analysis in Maternal Plasma: Theoretical and Empirical Considerations Clin. Chem., December 1, 2006; 52(12): 2194 - 2202. [Abstract] [Full Text] [PDF]
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 S. S. C. Chim, Y. K. Tong, R. W. K. Chiu, T. K. Lau, T. N. Leung, L. Y. S. Chan, C. B. M. Oudejans, C. Ding, and Y. M. D. Lo Detection of the placental epigenetic signature of the maspin gene in maternal plasma PNAS, October 11, 2005; 102(41): 14753 - 14758. [Abstract] [Full Text] [PDF]
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P. J. Bastian, G. S. Palapattu, X. Lin, S. Yegnasubramanian, L. A. Mangold, B. Trock, M. A. Eisenberger, A. W. Partin, and W. G. Nelson Preoperative Serum DNA GSTP1 CpG Island Hypermethylation and the Risk of Early Prostate-Specific Antigen Recurrence Following Radical Prostatectomy Clin. Cancer Res., June 1, 2005; 11(11): 4037 - 4043. [Abstract] [Full Text] [PDF]
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A. Benachi, A. Yamgnane, M. Olivi, Y. Dumez, E. Gautier, and J.-M. Costa Impact of Formaldehyde on the in Vitro Proportion of Fetal DNA in Maternal Plasma and Serum Clin. Chem., January 1, 2005; 51(1): 242 - 244. [Full Text] [PDF]
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 O. Gautschi, C. Bigosch, B. Huegli, M. Jermann, A. Marx, E. Chasse, D. Ratschiller, W. Weder, M. Joerger, D. C. Betticher, et al. Circulating Deoxyribonucleic Acid As Prognostic Marker in Non-Small-Cell Lung Cancer Patients Undergoing Chemotherapy J. Clin. Oncol., October 15, 2004; 22(20): 4157 - 4164. [Abstract] [Full Text] [PDF]
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 N B Y Tsui, S S C Chim, R W K Chiu, T K Lau, E K O Ng, T N Leung, Y K Tong, K C A Chan, and Y M D Lo Systematic micro-array based identification of placental mRNA in maternal plasma: towards non-invasive prenatal gene expression profiling J. Med. Genet., June 1, 2004; 41(6): 461 - 467. [Full Text] [PDF]
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Y. Li, B. Zimmermann, C. Rusterholz, A. Kang, W. Holzgreve, and S. Hahn Size Separation of Circulatory DNA in Maternal Plasma Permits Ready Detection of Fetal DNA Polymorphisms Clin. Chem., June 1, 2004; 50(6): 1002 - 1011. [Abstract] [Full Text] [PDF]
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T. Wataganara, E. S. LeShane, A. Y. Chen, L. Borgatta, I. Peter, K. L. Johnson, and D. W. Bianchi Plasma {gamma}-Globin Gene Expression Suggests that Fetal Hematopoietic Cells Contribute to the Pool of Circulating Cell-Free Fetal Nucleic Acids during Pregnancy Clin. Chem., April 1, 2004; 50(4): 689 - 693. [Abstract] [Full Text] [PDF]
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K.C. A. Chan, J. Zhang, A. B.Y. Hui, N. Wong, T. K. Lau, T. N. Leung, K.-W. Lo, D. W.S. Huang, and Y.M. D. Lo Size Distributions of Maternal and Fetal DNA in Maternal Plasma Clin. Chem., January 1, 2004; 50(1): 88 - 92. [Abstract] [Full Text] [PDF]
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N. Y.L. Lam, T. H. Rainer, R. W.K. Chiu, and Y.M. D. Lo EDTA Is a Better Anticoagulant than Heparin or Citrate for Delayed Blood Processing for Plasma DNA Analysis Clin. Chem., January 1, 2004; 50(1): 256 - 257. [Full Text] [PDF]
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 Y. Li, X. Y. Zhong, A. Kang, C. Troeger, W. Holzgreve, and S. Hahn Inability to Detect Cell Free Fetal DNA in the Urine of Normal Pregnant Women nor in Those Affected by Preeclampsia Associated HELLP Syndrome Reproductive Sciences, December 1, 2003; 10(8): 503 - 508. [Abstract] [PDF]
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M. Jung, S. Klotzek, M. Lewandowski, M. Fleischhacker, and K. Jung Changes in Concentration of DNA in Serum and Plasma during Storage of Blood Samples Clin. Chem., June 1, 2003; 49(6): 1028 - 1029. [Full Text] [PDF]
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M. H.M. Chan, K. M. Chow, A. T.C. Chan, C. B. Leung, L. Y.S. Chan, K. C.K. Chow, C. W. Lam, and Y.M. D. Lo Quantitative Analysis of Pleural Fluid Cell-free DNA as a Tool for the Classification of Pleural Effusions Clin. Chem., May 1, 2003; 49(5): 740 - 745. [Abstract] [Full Text] [PDF]
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E. K. O. Ng, N. B. Y. Tsui, T. K. Lau, T. N. Leung, R. W. K. Chiu, N. S. Panesar, L. C. W. Lit, K.-W. Chan, and Y. M. D. Lo From the Cover: mRNA of placental origin is readily detectable in maternal plasma PNAS, April 15, 2003; 100(8): 4748 - 4753. [Abstract] [Full Text] [PDF]
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Y. Y.N. Lui, K.-S. Woo, A. Y.M. Wang, C.-K. Yeung, P. K.T. Li, E. Chau, P. Ruygrok, and Y.M. D. Lo Origin of Plasma Cell-free DNA after Solid Organ Transplantation Clin. Chem., March 1, 2003; 49(3): 495 - 496. [Full Text] [PDF]
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I. H. N. Wong, J. Zhang, P. B. S. Lai, W. Y. Lau, and Y. M. Dennis Lo Quantitative Analysis of Tumor-derived Methylated p16INK4a Sequences in Plasma, Serum, and Blood Cells of Hepatocellular Carcinoma Patients Clin. Cancer Res., March 1, 2003; 9(3): 1047 - 1052. [Abstract] [Full Text] [PDF]
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Y. Y.N. Lui, K.-W. Chik, and Y.M. D. Lo Does Centrifugation Cause the ex Vivo Release of DNA from Blood Cells? Clin. Chem., November 1, 2002; 48(11): 2074 - 2076. [Full Text] [PDF]
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P. J. Johnson and Y.M. D. Lo Plasma Nucleic Acids in the Diagnosis and Management of Malignant Disease Clin. Chem., August 1, 2002; 48(8): 1186 - 1193. [Abstract] [Full Text] [PDF]
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E. K.O. Ng, N. B.Y. Tsui, N. Y.L. Lam, R. W.K. Chiu, S. C.H. Yu, S.C. C. Wong, E. S.F. Lo, T. H. Rainer, P. J. Johnson, and Y.M. D. Lo Presence of Filterable and Nonfilterable mRNA in the Plasma of Cancer Patients and Healthy Individuals Clin. Chem., August 1, 2002; 48(8): 1212 - 1217. [Abstract] [Full Text] [PDF]
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