The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB

Han, Diana; Ni, Meng; Chan, Rebecca Wing-Yan; Chan, Vicken W.; Lui, Kathy O.; Chiu, Rossa W.̉K.; Lo, Y.M. Dennis

doi:10.1016/j.ajhg.2020.01.008

Cited by 144 publications

(192 citation statements)

References 42 publications

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“…Hence, we propose that DNASE1L3 may play a role in the generation of plasma DNA end motifs. Our group is now exploring the effect of the deletion of genes coding for a number of the aforementioned nucleases on plasma DNA end motifs (25). Such ongoing work might shed new mechanistic insights into the generation of cf DNA end motifs.…”

Section: Discussionmentioning

confidence: 99%

Plasma DNA End-Motif Profiling as a Fragmentomic Marker in Cancer, Pregnancy, and Transplantation

et al. 2020

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There is much recent research interest in the molecular characteristics of cell-free DNA (cf DNA) in plasma. One such characteristic is the fragmentation patterns of cfDNA, including information regarding fragment sizes (1), nucleosome relationships (2, 3), and end points (4, 5). This area of research can be broadly named "fragmentomics" (6). cfDNA molecules are known to circulate as short fragments (1, 7) originating from different cell types, including various normal organ systems aBstRact Plasma DNA fragmentomics is an emerging area of research covering plasma DNA sizes, end points, and nucleosome footprints. In the present study, we found a significant increase in the diversity of plasma DNA end motifs in patients with hepatocellular carcinoma (HCC). Compared with patients without HCC, patients with HCC showed a preferential pattern of 4-mer end motifs. In particular, the abundance of plasma DNA motif CCCA was much lower in patients with HCC than in subjects without HCC. The aberrant end motifs were also observed in patients with other cancer types, including colorectal cancer, lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. We further observed that the profile of plasma DNA end motifs originating from the same organ, such as the liver, placenta, and hematopoietic cells, generally clustered together. The profile of end motifs may therefore serve as a class of biomarkers for liquid biopsy in oncology, noninvasive prenatal testing, and transplantation monitoring. SIGNIFICANCE: Plasma DNA molecules originating from the liver, HCC and other cancers, placenta, and hematopoietic cells each harbor a set of characteristic plasma DNA end motifs. Such markers carry tissueof-origin information and represent a new class of biomarkers in the nascent field of fragmentomics. Research.

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Section: Discussionmentioning

confidence: 99%

Plasma DNA End-Motif Profiling as a Fragmentomic Marker in Cancer, Pregnancy, and Transplantation

et al. 2020

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“…As DNA nucleases have been reported to be responsible for plasma DNA end motifs (Serpas et al 2019;Han et al 2020;Jiang et al 2020), we studied whether jaggedness of plasma DNA, as a new fragmentomic marker, could be used as an indicator reflecting DNASE1L3 and DNASE1 activities using mouse models with the deletion of different nucleases. To this end, we measured the jaggedness index in wild type (n = 12), Dnase1 −/− (n = 7), and Dnase1l3 −/− (n = 5), with the use of the filling of methylated cytosines.…”

Section: Biological Implications Of Plasma Dna Jaggednessmentioning

confidence: 99%

“…The down-regulation of DNASE1L3 in hepatocellular carcinoma (HCC) tumor tissues coincided with the reduction of the CCCA end motif in plasma of patients with HCC (Jiang et al 2020), resembling the consequence of Dnase1l3-deficient mice. In addition, different nucleases such as DNASE1 and DNASElL3 may be responsible for different cutting patterns with regard to the ends of cell-free DNA (Han et al 2020). The discovery of new biological properties is a catalyst for new diagnostic approaches.…”

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Detection and characterization of jagged ends of double-stranded DNA in plasma

et al. 2020

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Cell-free DNA in plasma has been used for noninvasive prenatal testing and cancer liquid biopsy. The physical properties of cell-free DNA fragments in plasma, such as fragment sizes and ends, have attracted much recent interest, leading to the emerging field of cell-free DNA fragmentomics. However, one aspect of plasma DNA fragmentomics as to whether double-stranded plasma molecules might carry single-stranded ends, termed a jagged end in this study, remains underexplored. We have developed two approaches for investigating the presence of jagged ends in a plasma DNA pool. These approaches utilized DNA end repair to introduce differential methylation signals between the original sequence and the jagged ends, depending on whether unmethylated or methylated cytosines were used in the DNA end-repair procedure. The majority of plasma DNA molecules (87.8%) were found to bear jagged ends. The jaggedness varied according to plasma DNA fragment sizes and appeared to be in association with nucleosomal patterns. In the plasma of pregnant women, the jaggedness of fetal DNA molecules was higher than that of the maternal counterparts. The jaggedness of plasma DNA correlated with the fetal DNA fraction. Similarly, in the plasma of cancer patients, tumor-derived DNA molecules in patients with hepatocellular carcinoma showed an elevated jaggedness compared with nontumoral DNA. In mouse models, knocking out of the Dnase1 gene reduced jaggedness, whereas knocking out of the Dnase1l3 gene enhanced jaggedness. Hence, plasma DNA jagged ends represent an intrinsic property of plasma DNA and provide a link between nuclease activities and the fragmentation of plasma DNA.

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“…DFFB participates in nucleic acid metabolism and is mainly involved in DNA replication and repair, transcription regulation, etc. 20 DFFB is also a crucial protein in the apoptotic pathway, triggering both DNA fragmentation and chromatin condensation during this process. Although there are relatively few studies on the correlation between HNRNPCL1, PRAMEF1, CFAP74, and DFFB and tumors, these mutation sites on the four genes identified in this study had annotation information in the COSMIC database.…”

Section: Discussionmentioning

confidence: 99%

HNRNPCL1, PRAMEF1, CFAP74, and DFFB: Common Potential Biomarkers for Sporadic and Suspected Lynch Syndrome Endometrial Cancer

Gao

Zhang

et al. 2020

CMAR

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To investigate the genes of patients with sporadic endometrial cancer (EC) and suspected Lynch syndrome (LS)-related EC in the Chinese population. Identification of meaningful mutation sites can provide theoretical basis for molecular targeted therapy, aiming to improve the prognosis of patients with EC. Methods: We recruited 388 patients with EC for mismatch repair (MMR) immunohistochemistry and MLH1 methylation analysis. Based on the results, they were divided into four groups: MMR without deletion group (sporadic EC group 1); MLH1&PMS2 deletion and MLH1 methylation group (sporadic EC group 2); MSH2 and/or MSH6 deletion group (suspected LS group); and unclassified group (remainder cases). Patients from each group were randomly screened for whole-exome sequencing detection. Genome Analysis Toolkit, VarScant, MuTect, and CONTRA were used to detect the insertions/deletions, single nucleotide polymorphisms, and copy number variations. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed with Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction analysis was accomplished through the STRING database. Results: The MMR immunohistochemistry results were positive (without MMR deletion) and negative in 299 patients and 89 patients, respectively. The 32, 10, 13, and 7 patients in the sporadic EC group 1, sporadic EC group 2, suspected LS group, and unclassified group were randomly selected for whole-exome sequencing, respectively. These three groups had a total of 86 common mutation sites, which were distributed on 26 genes. Among the top 30 common high-frequency mutation sites, 12, 5, 4, and 3 mutation sites were located on HNRNPCL1, PRAMEF1, HNRNPCL2, and CFAP74, respectively. Protein-protein interaction analysis showed that DFFB was associated with the most genes. There were some differences in the number of specific mutations in the families of different LS-related EC proband. Conclusion: HNRNPCL1, PRAMEF1, CFAP74, and DFFB may be potential biomarkers for EC or LS-related EC.

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The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB

Cited by 144 publications

References 42 publications

Plasma DNA End-Motif Profiling as a Fragmentomic Marker in Cancer, Pregnancy, and Transplantation

Plasma DNA End-Motif Profiling as a Fragmentomic Marker in Cancer, Pregnancy, and Transplantation

Detection and characterization of jagged ends of double-stranded DNA in plasma

<p><em>HNRNPCL1</em>, <em>PRAMEF1</em>, <em>CFAP74</em>, and <em>DFFB</em>: Common Potential Biomarkers for Sporadic and Suspected Lynch Syndrome Endometrial Cancer</p>

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