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Article ; Online: Cell-Free DNA Fragmentomics in Liquid Biopsy

Spencer C. Ding / Y.M. Dennis Lo

Diagnostics, Vol 12, Iss 978, p

2022 Volume 978

Abstract: Cell-free DNA (cfDNA) in bodily fluids has rapidly transformed the development of noninvasive prenatal testing, cancer liquid biopsy, and transplantation monitoring. Plasma cfDNA consists of a mixture of molecules originating from various bodily tissues. ...

Abstract	Cell-free DNA (cfDNA) in bodily fluids has rapidly transformed the development of noninvasive prenatal testing, cancer liquid biopsy, and transplantation monitoring. Plasma cfDNA consists of a mixture of molecules originating from various bodily tissues. The study of the fragmentation patterns of cfDNA, also referred to as ‘fragmentomics’, is now an actively pursued area of biomarker research. Clues that cfDNA fragmentation patterns might carry information concerning the tissue of origin of cfDNA molecules have come from works demonstrating that circulating fetal, tumor-derived, and transplanted liver-derived cfDNA molecules have a shorter size distribution than the background mainly of hematopoietic origin. More recently, an improved understanding of cfDNA fragmentation has provided many emerging fragmentomic markers, including fragment sizes, preferred ends, end motifs, single-stranded jagged ends, and nucleosomal footprints. The intrinsic biological link between activities of various DNA nucleases and characteristic fragmentations has been demonstrated. In this review, we focus on the biological properties of cell-free DNA unveiled recently and their potential clinical applications.
Keywords	cell-free DNA ; NIPT ; liquid biopsy ; cancer detection ; fragmentomics ; Medicine (General) ; R5-920
Subject code	612
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High-resolution analysis for urinary DNA jagged ends

Tingting Xie / Guangya Wang / Spencer C. Ding / Wing-Shan Lee / Suk Hang Cheng / Rebecca W. Y. Chan / Ze Zhou / Mary-Jane L. Ma / Diana S. C. Han / Jeremy Y. C. Teoh / W. K. Jacky Lam / Peiyong Jiang / Rossa W. K. Chiu / K. C. Allen Chan / Y. M. Dennis Lo

npj Genomic Medicine, Vol 7, Iss 1, Pp 1-

2022 Volume 8

Abstract: Abstract Single-stranded ends of double-stranded DNA (jagged ends) are more abundant in urinary DNA than in plasma DNA. However, the lengths of jagged ends in urinary DNA remained undetermined, as a previous method used for urinary DNA jagged end ... ...

Abstract	Abstract Single-stranded ends of double-stranded DNA (jagged ends) are more abundant in urinary DNA than in plasma DNA. However, the lengths of jagged ends in urinary DNA remained undetermined, as a previous method used for urinary DNA jagged end sequencing analysis (Jag-seq) relied on unmethylation at CpG sites, limiting the resolution. Here, we performed high-resolution Jag-seq analysis using methylation at non-CpG cytosine sites, allowing determination of exact length of jagged ends. The urinary DNA bore longer jagged ends (~26-nt) than plasma DNA (~17-nt). The jagged end length distribution displayed 10-nt periodicities in urinary DNA, which were much less observable in plasma DNA. Amplitude of the 10-nt periodicities increased in patients with renal cell carcinoma. Heparin treatment of urine diminished the 10-nt periodicities. The urinary DNA jagged ends often extended into nucleosomal cores, suggesting potential interactions with histones. This study has thus advanced our knowledge of jagged ends in urine DNA.
Keywords	Medicine ; R ; Genetics ; QH426-470
Subject code	612
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effects of nucleases on cell-free extrachromosomal circular DNA

Sarah T.K. Sin / Jiaen Deng / Lu Ji / Masashi Yukawa / Rebecca W.Y. Chan / Stefano Volpi / Augusto Vaglio / Paride Fenaroli / Paola Bocca / Suk Hang Cheng / Danny K.L. Wong / Kathy O. Lui / Peiyong Jiang / K.C. Allen Chan / Rossa W.K. Chiu / Y.M. Dennis Lo

JCI Insight, Vol 7, Iss

2022 Volume 8

Abstract: Cell-free extrachromosomal circular DNA (eccDNA) as a distinct topological form from linear DNA has recently gained increasing research interest, with possible clinical applications as a class of biomarkers. In this study, we aimed to explore the ... ...

Abstract	Cell-free extrachromosomal circular DNA (eccDNA) as a distinct topological form from linear DNA has recently gained increasing research interest, with possible clinical applications as a class of biomarkers. In this study, we aimed to explore the relationship between nucleases and eccDNA characteristics in plasma. By using knockout mouse models with deficiencies in deoxyribonuclease 1 (DNASE1) or deoxyribonuclease 1 like 3 (DNASE1L3), we found that cell-free eccDNA in Dnase1l3−/− mice exhibited larger size distributions than that in wild-type mice. Such size alterations were not found in tissue eccDNA of either Dnase1−/− or Dnase1l3−/− mice, suggesting that DNASE1L3 could digest eccDNA extracellularly but did not seem to affect intracellular eccDNA. Using a mouse pregnancy model, we observed that in Dnase1l3−/− mice pregnant with Dnase1l3+/− fetuses, the eccDNA in the maternal plasma was shorter compared with that of Dnase1l3−/− mice carrying Dnase1l3−/− fetuses, highlighting the systemic effects of circulating fetal DNASE1L3 degrading the maternal eccDNA extracellularly. Furthermore, plasma eccDNA in patients with DNASE1L3 mutations also exhibited longer size distributions than that in healthy controls. Taken together, this study provided a hitherto missing link between nuclease activity and the biological manifestations of eccDNA in plasma, paving the way for future biomarker development of this special form of DNA molecules.
Keywords	Genetics ; Medicine ; R
Subject code	612
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases

W. K. Jacky Lam / Peiyong Jiang / K. C. Allen Chan / Wenlei Peng / Huimin Shang / Macy M. S. Heung / Suk Hang Cheng / Haiqiang Zhang / O. Y. Olivia Tse / Radha Raghupathy / Brigette B. Y. Ma / Edwin P. Hui / Anthony T. C. Chan / John K. S. Woo / Rossa W. K. Chiu / Y. M. Dennis Lo

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 11

Abstract: Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can ...

Abstract	Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
Keywords	Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 11

Abstract	Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
Keywords	Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methy-Pipe

Peiyong Jiang / Kun Sun / Fiona M F Lun / Andy M Guo / Huating Wang / K C Allen Chan / Rossa W K Chiu / Y M Dennis Lo / Hao Sun

PLoS ONE, Vol 9, Iss 6, p e

an integrated bioinformatics pipeline for whole genome bisulfite sequencing data analysis.

2014 Volume 100360

Abstract: DNA methylation, one of the most important epigenetic modifications, plays a crucial role in various biological processes. The level of DNA methylation can be measured using whole-genome bisulfite sequencing at single base resolution. However, until now, ...

Abstract	DNA methylation, one of the most important epigenetic modifications, plays a crucial role in various biological processes. The level of DNA methylation can be measured using whole-genome bisulfite sequencing at single base resolution. However, until now, there is a paucity of publicly available software for carrying out integrated methylation data analysis. In this study, we implemented Methy-Pipe, which not only fulfills the core data analysis requirements (e.g. sequence alignment, differential methylation analysis, etc.) but also provides useful tools for methylation data annotation and visualization. Specifically, it uses Burrow-Wheeler Transform (BWT) algorithm to directly align bisulfite sequencing reads to a reference genome and implements a novel sliding window based approach with statistical methods for the identification of differentially methylated regions (DMRs). The capability of processing data parallelly allows it to outperform a number of other bisulfite alignment software packages. To demonstrate its utility and performance, we applied it to both real and simulated bisulfite sequencing datasets. The results indicate that Methy-Pipe can accurately estimate methylation densities, identify DMRs and provide a variety of utility programs for downstream methylation data analysis. In summary, Methy-Pipe is a useful pipeline that can process whole genome bisulfite sequencing data in an efficient, accurate, and user-friendly manner. Software and test dataset are available at http://sunlab.lihs.cuhk.edu.hk/methy-pipe/.
Keywords	Medicine ; R ; Science ; Q
Subject code	310
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Noninvasive prenatal diagnosis of fetal trisomy 21 by allelic ratio analysis using targeted massively parallel sequencing of maternal plasma DNA.

Gary J W Liao / K C Allen Chan / Peiyong Jiang / Hao Sun / Tak Y Leung / Rossa W K Chiu / Y M Dennis Lo

PLoS ONE, Vol 7, Iss 5, p e

2012 Volume 38154

Abstract: BACKGROUND: Plasma DNA obtained from a pregnant woman contains a mixture of maternal and fetal DNA. The fetal DNA proportion in maternal plasma is relatively consistent as determined using polymorphic genetic markers across different chromosomes in ... ...

Abstract	BACKGROUND: Plasma DNA obtained from a pregnant woman contains a mixture of maternal and fetal DNA. The fetal DNA proportion in maternal plasma is relatively consistent as determined using polymorphic genetic markers across different chromosomes in euploid pregnancies. For aneuploid pregnancies, the observed fetal DNA proportion measured using polymorphic genetic markers for the aneuploid chromosome would be perturbed. In this study, we investigated the feasibility of analyzing single nucleotide polymorphisms using targeted massively parallel sequencing to detect such perturbations in mothers carrying trisomy 21 fetuses. METHODOLOGY/PRINCIPAL FINDINGS: DNA was extracted from plasma samples collected from fourteen pregnant women carrying singleton fetuses. Hybridization-based targeted sequencing was used to enrich 2 906 single nucleotide polymorphism loci on chr7, chr13, chr18 and chr21. Plasma DNA libraries with and without target enrichment were analyzed by massively parallel sequencing. Genomic DNA samples of both the mother and fetus for each case were genotyped by single nucleotide polymorphism microarray analysis. For the targeted regions, the mean sequencing depth of the enriched samples was 225-fold higher than that of the non-enriched samples. From the targeted sequencing data, the ratio between fetus-specific and shared alleles increased by approximately 2-fold on chr21 in the paternally-derived trisomy 21 case. In comparison, the ratio is decreased by approximately 11% on chr21 in the maternally-derived trisomy 21 cases but with much overlap with the ratio of the euploid cases. Computer simulation revealed the relationship between the fetal DNA proportion, the number of informative alleles and the depth of sequencing. CONCLUSIONS/SIGNIFICANCE: Targeted massively parallel sequencing of single nucleotide polymorphism loci in maternal plasma DNA is a potential approach for trisomy 21 detection. However, the method appears to be less robust than approaches using non-polymorphism-based counting of sequence ...
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High resolution size analysis of fetal DNA in the urine of pregnant women by paired-end massively parallel sequencing.

Nancy B Y Tsui / Peiyong Jiang / Katherine C K Chow / Xiaoxi Su / Tak Y Leung / Hao Sun / K C Allen Chan / Rossa W K Chiu / Y M Dennis Lo

PLoS ONE, Vol 7, Iss 10, p e

2012 Volume 48319

Abstract: BACKGROUND: Fetal DNA in maternal urine, if present, would be a valuable source of fetal genetic material for noninvasive prenatal diagnosis. However, the existence of fetal DNA in maternal urine has remained controversial. The issue is due to the lack ... ...

Abstract	BACKGROUND: Fetal DNA in maternal urine, if present, would be a valuable source of fetal genetic material for noninvasive prenatal diagnosis. However, the existence of fetal DNA in maternal urine has remained controversial. The issue is due to the lack of appropriate technology to robustly detect the potentially highly degraded fetal DNA in maternal urine. METHODOLOGY: We have used massively parallel paired-end sequencing to investigate cell-free DNA molecules in maternal urine. Catheterized urine samples were collected from seven pregnant women during the third trimester of pregnancies. We detected fetal DNA by identifying sequenced reads that contained fetal-specific alleles of the single nucleotide polymorphisms. The sizes of individual urinary DNA fragments were deduced from the alignment positions of the paired reads. We measured the fractional fetal DNA concentration as well as the size distributions of fetal and maternal DNA in maternal urine. PRINCIPAL FINDINGS: Cell-free fetal DNA was detected in five of the seven maternal urine samples, with the fractional fetal DNA concentrations ranged from 1.92% to 4.73%. Fetal DNA became undetectable in maternal urine after delivery. The total urinary cell-free DNA molecules were less intact when compared with plasma DNA. Urinary fetal DNA fragments were very short, and the most dominant fetal sequences were between 29 bp and 45 bp in length. CONCLUSIONS: With the use of massively parallel sequencing, we have confirmed the existence of transrenal fetal DNA in maternal urine, and have shown that urinary fetal DNA was heavily degraded.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 612
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epigenetic-genetic chromosome dosage approach for fetal trisomy 21 detection using an autosomal genetic reference marker.

Yu K Tong / Rossa W K Chiu / Ranjit Akolekar / Tak Y Leung / Tze K Lau / Kypros H Nicolaides / Y M Dennis Lo

PLoS ONE, Vol 5, Iss 12, p e

2010 Volume 15244

Abstract: BACKGROUND: The putative promoter of the holocarboxylase synthetase (HLCS) gene on chromosome 21 is hypermethylated in placental tissues and could be detected as a fetal-specific DNA marker in maternal plasma. Detection of fetal trisomy 21 (T21) has been ...

Abstract	BACKGROUND: The putative promoter of the holocarboxylase synthetase (HLCS) gene on chromosome 21 is hypermethylated in placental tissues and could be detected as a fetal-specific DNA marker in maternal plasma. Detection of fetal trisomy 21 (T21) has been demonstrated by an epigenetic-genetic chromosome dosage approach where the amount of hypermethylated HLCS in maternal plasma is normalized using a fetal genetic marker on the Y chromosome as a chromosome dosage reference marker. We explore if this method can be applied on both male and female fetuses with the use of a paternally-inherited fetal single nucleotide polymorphism (SNP) allele on a reference chromosome for chromosome dosage normalization. METHODOLOGY: We quantified hypermethylated HLCS molecules using methylation-sensitive restriction endonuclease digestion followed by real-time or digital PCR analyses. For chromosome dosage analysis, we compared the amount of digestion-resistant HLCS to that of a SNP allele (rs6636, a C/G SNP) that the fetus has inherited from the father but absent in the pregnant mother. PRINCIPAL FINDINGS: Using a fetal-specific SNP allele on a reference chromosome, we analyzed 20 euploid and nine T21 placental tissue samples. All samples with the fetal-specific C allele were correctly classified. One sample from each of the euploid and T21 groups were misclassified when the fetal-specific G allele was used as the reference marker. We then analyzed 33 euploid and 14 T21 maternal plasma samples. All but one sample from each of the euploid and T21 groups were correctly classified using the fetal-specific C allele, while correct classification was achieved for all samples using the fetal-specific G allele as the reference marker. CONCLUSIONS: As a proof-of-concept study, we have demonstrated that the epigenetic-genetic chromosome dosage approach can be applied to the prenatal diagnosis of trisomy 21 for both male and female fetuses.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2010-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Placenta-derived fetal specific mRNA is more readily detectable in maternal plasma than in whole blood.

Macy M S Heung / Shengnan Jin / Nancy B Y Tsui / Chunming Ding / Tak Y Leung / Tze K Lau / Rossa W K Chiu / Y M Dennis Lo

PLoS ONE, Vol 4, Iss 6, p e

2009 Volume 5858

Abstract: BACKGROUND:Placental mRNA was detected in maternal whole blood, raising the possibility of using maternal blood for noninvasive prenatal diagnosis. We investigated fetal mRNA detection in maternal whole blood and determined if it offered advantages over ... ...

Abstract	BACKGROUND:Placental mRNA was detected in maternal whole blood, raising the possibility of using maternal blood for noninvasive prenatal diagnosis. We investigated fetal mRNA detection in maternal whole blood and determined if it offered advantages over maternal plasma analysis. METHODOLOGY:The concentrations of placental expressed genes, CSH1, KISS1, PLAC4 and PLAC1 in plasma and whole blood from healthy pregnant and non-pregnant individuals were compared by real-time quantitative reverse-transcriptase polymerase chain reaction analysis. Their fetal specificity was investigated by comparing the transcript concentrations in pre- and post-delivery samples and through SNP genotyping by matrix-assisted laser-desorption and ionization time-of-flight mass spectrometry. The gene expression profiles of pregnant and non-pregnant whole blood were investigated by microarray analysis. Upregulated genes in pregnant whole blood were selected for further quantitative analysis. PRINCIPAL FINDINGS:The concentrations of the four transcripts were significantly higher in third trimester maternal whole blood than corresponding plasma without significant correlations. KISS1, PLAC4 and PLAC1 were detected in non-pregnant whole blood but not plasma. The transcripts remained detectable in some postpartum whole blood samples. The PLAC4 mRNA in maternal plasma showed fetal genotype while that in corresponding whole blood indicated both fetal and maternal contributions. Microarray analysis revealed upregulation of genes involved in neutrophil functions in pregnant whole blood including DEFA4, CEACAM8, OLFM4, ORM1, MMP8 and MPO. Though possibly pregnancy-related, they were not pregnancy-specific as suggested by the lack of post-delivery reduction in concentrations. CONCLUSIONS:Maternal plasma is preferred over maternal whole blood for placenta-derived fetal RNA detection. Most studied 'placental' mRNA molecules in maternal whole blood were of maternal origin and might be derived from processes such as 'illegitimate transcription'.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2009-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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