Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs
Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as "founder" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 120(2023), 17 vom: 25. Apr., Seite e2220982120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhou, Ze [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.04.2023 Date Revised 09.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2220982120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM355789159 |
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| 100 | 1 | |a Zhou, Ze |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 21.04.2023 | ||
| 500 | |a Date Revised 09.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as "founder" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cancer detection | |
| 650 | 4 | |a fragmentomics | |
| 650 | 4 | |a liquid biopsy | |
| 650 | 4 | |a non-negative matrix factorization | |
| 650 | 4 | |a oxidative stress | |
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| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a Endodeoxyribonucleases |2 NLM | |
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| 700 | 1 | |a Ma, Mary-Jane L |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Rebecca W Y |e verfasserin |4 aut | |
| 700 | 1 | |a Lam, W K Jacky |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Wenlei |e verfasserin |4 aut | |
| 700 | 1 | |a Gai, Wanxia |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Spencer C |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Cheung, Peter P H |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Stephanie C Y |e verfasserin |4 aut | |
| 700 | 1 | |a Teoh, Jeremy Y C |e verfasserin |4 aut | |
| 700 | 1 | |a Szeto, Cheuk-Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, John |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Vincent W S |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Grace L H |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Stephen L |e verfasserin |4 aut | |
| 700 | 1 | |a Hui, Edwin P |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Brigette B Y |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Anthony T C |e verfasserin |4 aut | |
| 700 | 1 | |a Chiu, Rossa W K |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, K C Allen |e verfasserin |4 aut | |
| 700 | 1 | |a Lo, Y M Dennis |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Peiyong |e verfasserin |4 aut | |
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