Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20:71–88. https://doi.org/10.1038/s41576-018-0071-5.
Article
CAS
Google Scholar
Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature. 2019;570:385–9. https://doi.org/10.1038/s41586-019-1272-6.
Article
CAS
Google Scholar
Chabon JJ, Hamilton EG, Kurtz DM, Esfahani MS, Moding EJ, Stehr H, et al. Integrating genomic features for non-invasive early lung cancer detection. Nature. 2020;580:245–51. https://doi.org/10.1038/s41586-020-2140-0.
Article
CAS
Google Scholar
Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS One. 2011;6:e23418. https://doi.org/10.1371/journal.pone.0023418.
Article
CAS
Google Scholar
Liu Y. At the dawn: cell-free DNA fragmentomics and gene regulation. Br J Cancer. 2022;126:379–90. https://doi.org/10.1038/s41416-021-01635-z.
Article
CAS
Google Scholar
Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell. 2016;164:57–68. https://doi.org/10.1016/j.cell.2015.11.050.
Article
CAS
Google Scholar
Ulz P, Thallinger GG, Auer M, Graf R, Kashofer K, Jahn SW, et al. Inferring expressed genes by whole-genome sequencing of plasma DNA. Nat Genet. 2016;48:1273–8. https://doi.org/10.1038/ng.3648.
Article
CAS
Google Scholar
Jiang P, Sun K, Tong YK, Cheng SH, Cheng THT, Heung MMS, et al. Preferred end coordinates and somatic variants as signatures of circulating tumor DNA associated with hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2018;115:E10925–33. https://doi.org/10.1073/pnas.1814616115.
Article
CAS
Google Scholar
Sun K, Jiang P, Cheng SH, Cheng THT, Wong J, Wong VWS, et al. Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin. Genome Res. 2019;29:418–27. https://doi.org/10.1101/gr.242719.118.
Article
CAS
Google Scholar
Ulz P, Perakis S, Zhou Q, Moser T, Belic J, Lazzeri I, et al. Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection. Nat Commun. 2019;10:4666. https://doi.org/10.1038/s41467-019-12714-4.
Article
CAS
Google Scholar
Jiang P, Sun K, Peng W, Cheng SH, Ni M, Yeung PC, et al. Plasma DNA end-motif profiling as a fragmentomic marker in cancer, pregnancy, and transplantation. Cancer Discov. 2020;10:664–73. https://doi.org/10.1158/2159-8290.CD-19-0622.
Article
CAS
Google Scholar
Zhu G, Guo YA, Ho D, Poon P, Poh ZW, Wong PM, et al. Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden. Nat Commun. 2021;12:2229. https://doi.org/10.1038/s41467-021-22463-y.
Article
CAS
Google Scholar
Peneder P, Stütz AM, Surdez D, Krumbholz M, Semper S, Chicard M, et al. Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden. Nat Commun. 2021;12:3230. https://doi.org/10.1038/s41467-021-23445-w.
Article
CAS
Google Scholar
Mathios D, Johansen JS, Cristiano S, Medina JE, Phallen J, Larsen KR, et al. Detection and characterization of lung cancer using cell-free DNA fragmentomes. Nat Commun. 2021;12:5060. https://doi.org/10.1038/s41467-021-24994-w.
Article
CAS
Google Scholar
Corces MR, Granja JM, Shams S, Louie BH, Seoane JA, Zhou W, et al. The chromatin accessibility landscape of primary human cancers. Science. 2018:362. https://doi.org/10.1126/science.aav1898.
Calderon D, Nguyen MLT, Mezger A, Kathiria A, Müller F, Nguyen V, et al. Landscape of stimulation-responsive chromatin across diverse human immune cells. Nat Genet. 2019;51:1494–505. https://doi.org/10.1038/s41588-019-0505-9.
Article
CAS
Google Scholar
Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. The human transcription factors. Cell. 2018;172:650–65. https://doi.org/10.1016/j.cell.2018.01.029.
Article
CAS
Google Scholar
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20. https://doi.org/10.1093/bioinformatics/btu170.
Article
CAS
Google Scholar
Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25:1754–60. https://doi.org/10.1093/bioinformatics/btp324.
Article
CAS
Google Scholar
Faust GG, Hall IM. SAMBLASTER: fast duplicate marking and structural variant read extraction. Bioinformatics. 2014;30:2503–5. https://doi.org/10.1093/bioinformatics/btu314.
Article
CAS
Google Scholar
Sun K, Jiang P, Chan KCA, Wong J, Cheng YKY, Liang RHS, et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci U S A. 2015;112:E5503–12. https://doi.org/10.1073/pnas.1508736112.
Article
CAS
Google Scholar
Chan KCA, Jiang P, Chan CWM, Sun K, Wong J, Hui EP, et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci U S A. 2013;110:18761–8. https://doi.org/10.1073/pnas.1313995110.
Article
CAS
Google Scholar
Krueger F. Trim galore. A wrapper tool around Cutadapt and FastQC to consistently apply quality and adapter trimming to FastQ files. 2015;516:517.
Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J EMBnet Stichting. 2011;17:10. https://doi.org/10.14806/ej.17.1.200.
Article
Google Scholar
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9. https://doi.org/10.1093/bioinformatics/btp352.
Article
CAS
Google Scholar
Liu Y, Siegmund KD, Laird PW, Berman BP. Bis-SNP: combined DNA methylation and SNP calling for bisulfite-seq data. Genome Biol. 2012;13:R61. https://doi.org/10.1186/gb-2012-13-7-r61.
Article
CAS
Google Scholar
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137. https://doi.org/10.1186/gb-2008-9-9-r137.
Article
CAS
Google Scholar
Derrien T, Estellé J, Sola SM, Knowles DG, Raineri E, Guigó R, et al. Fast computation and applications of genome mappability. PLoS One. 2012;7:e30377 Public Library of Science; [cited 2020 Jul 1]. https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0030377&type=printable.
Article
CAS
Google Scholar
Ji H, Jiang H, Ma W, Johnson DS, Myers RM, Wong WH. An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nat Biotechnol. 2008;26:1293–300. https://doi.org/10.1038/nbt.1505.
Article
CAS
Google Scholar
Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–30. https://doi.org/10.1038/nature14248.
Article
CAS
Google Scholar
Benjamini Y, Speed TP. Summarizing and correcting the GC content bias in high-throughput sequencing. Nucleic Acids Res. 2012;40:e72. https://doi.org/10.1093/nar/gks001.
Article
CAS
Google Scholar
Chandrananda D, Thorne NP, Ganesamoorthy D, Bruno DL, Benjamini Y, Speed TP, et al. Investigating and correcting plasma DNA sequencing coverage bias to enhance aneuploidy discovery. PLoS One. 2014;9:e86993. https://doi.org/10.1371/journal.pone.0086993.
Article
CAS
Google Scholar
Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10:1213–8. https://doi.org/10.1038/nmeth.2688.
Article
CAS
Google Scholar
Lui YYN, Chik K-W, Chiu RWK, Ho C-Y, Lam CWK, Lo YMD. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem. 2002;48:421–7 https://www.ncbi.nlm.nih.gov/pubmed/11861434.
Article
CAS
Google Scholar
Moss J, Magenheim J, Neiman D, Zemmour H, Loyfer N, Korach A, et al. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease. Nat Commun. 2018;9:5068. https://doi.org/10.1038/s41467-018-07466-6.
Article
CAS
Google Scholar
Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034–50. https://doi.org/10.1101/gr.3715005.
Article
CAS
Google Scholar
ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74. https://doi.org/10.1038/nature11247.
Article
CAS
Google Scholar
Stunnenberg HG, International Human Epigenome Consortium, Hirst M. The international human Epigenome consortium: a blueprint for scientific collaboration and discovery. Cell. 2016;167:1145–9. https://doi.org/10.1016/j.cell.2016.11.007.
Article
CAS
Google Scholar
Corces MR, Buenrostro JD, Wu B, Greenside PG, Chan SM, Koenig JL, et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat Genet. 2016;48:1193–203. https://doi.org/10.1038/ng.3646.
Article
CAS
Google Scholar
Soufi A, Garcia MF, Jaroszewicz A, Osman N, Pellegrini M, Zaret KS. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell. 2015;161:555–68. https://doi.org/10.1016/j.cell.2015.03.017.
Article
CAS
Google Scholar
Jiang P, Chan CWM, Chan KCA, Cheng SH, Wong J, Wong VW-S, et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015;112:E1317–25. https://doi.org/10.1073/pnas.1500076112.
Article
CAS
Google Scholar
Zheng H, Zhu MS, Liu Y. FinaleDB: a browser and database of cell-free DNA fragmentation patterns. Bioinformatics. 2021;37:2502–3. https://doi.org/10.1093/bioinformatics/btaa999.
Article
CAS
Google Scholar
Li S, Wan C, Zheng R, Fan J, Dong X, Meyer CA, et al. Cistrome-GO: a web server for functional enrichment analysis of transcription factor ChIP-seq peaks. Nucleic Acids Res. 2019;47:W206–11. https://doi.org/10.1093/nar/gkz332.
Article
CAS
Google Scholar
Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang H-Y, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–24. https://doi.org/10.1053/j.gastro.2008.12.004.
Article
CAS
Google Scholar
Terris B, Cavard C, Perret C. EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. J Hepatol. 2010;52:280–1. https://doi.org/10.1016/j.jhep.2009.10.026.
Article
CAS
Google Scholar
Kos J, Werle B, Lah T, Brunner N. Cysteine proteinases and their inhibitors in extracellular fluids: markers for diagnosis and prognosis in cancer. Int J Biol Markers. 2000;15:84–9 https://www.ncbi.nlm.nih.gov/pubmed/10763147.
Article
CAS
Google Scholar
Su W-J, Lu P-Z, Wu Y, Kalpana K, Yang C-K, Lu G-D. Identification of key genes in purine metabolism as prognostic biomarker for hepatocellular carcinoma. Front Oncol. 2020;10:583053. https://doi.org/10.3389/fonc.2020.583053.
Article
Google Scholar
Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359:926–30. https://doi.org/10.1126/science.aar3247.
Article
CAS
Google Scholar
Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, Liu MC, et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020; http://www.sciencedirect.com/science/article/pii/S0923753420360580.
Wan N, Weinberg D, Liu T-Y, Niehaus K, Ariazi EA, Delubac D, et al. Machine learning enables detection of early-stage colorectal cancer by whole-genome sequencing of plasma cell-free DNA. BMC Cancer. 2019;19:832. https://doi.org/10.1186/s12885-019-6003-8.
Article
CAS
Google Scholar
Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature. 2018;563:579–83. https://doi.org/10.1038/s41586-018-0703-0.
Article
CAS
Google Scholar
Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun. 2017;8:1324. https://doi.org/10.1038/s41467-017-00965-y.
Article
CAS
Google Scholar
Zviran A, Schulman RC, Shah M, Hill STK, Deochand S, Khamnei CC, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020;26:1114–24. https://doi.org/10.1038/s41591-020-0915-3.
Article
CAS
Google Scholar
Liu EM, Martinez-Fundichely A, Diaz BJ, Aronson B, Cuykendall T, MacKay M, et al. Identification of cancer drivers at CTCF insulators in 1,962 whole genomes. Cell Syst. 2019;8:446–455.e8. https://doi.org/10.1016/j.cels.2019.04.001.
Article
CAS
Google Scholar
Khurana E, Fu Y, Chakravarty D, Demichelis F, Rubin MA, Gerstein M. Role of non-coding sequence variants in cancer. Nat Rev Genet. 2016;17:93–108. https://doi.org/10.1038/nrg.2015.17.
Article
CAS
Google Scholar
Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018;32:1267–84. https://doi.org/10.1101/gad.314617.118.
Article
CAS
Google Scholar
Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21:345–59. https://doi.org/10.1038/s41568-021-00347-z.
Article
CAS
Google Scholar
Jensen TJ, Kim SK, Zhu Z, Chin C, Gebhard C, Lu T, et al. Whole genome bisulfite sequencing of cell-free DNA and its cellular contributors uncovers placenta hypomethylated domains. Genome Biol. 2015;16:78. https://doi.org/10.1186/s13059-015-0645-x.
Article
CAS
Google Scholar
Ivanov M, Baranova A, Butler T, Spellman P, Mileyko V. Non-random fragmentation patterns in circulating cell-free DNA reflect epigenetic regulation. BMC Genomics. 2015;16(Suppl 13):S1. https://doi.org/10.1186/1471-2164-16-S13-S1.
Article
Google Scholar
Cheung M-S, Down TA, Latorre I, Ahringer J. Systematic bias in high-throughput sequencing data and its correction by BEADS. Nucleic Acids Res. 2011;39:e103. https://doi.org/10.1093/nar/gkr425.
Article
CAS
Google Scholar
Mammana A, Vingron M, Chung H-R. Inferring nucleosome positions with their histone mark annotation from ChIP data. Bioinformatics. 2013;29:2547–54. https://doi.org/10.1093/bioinformatics/btt449.
Article
CAS
Google Scholar
Teng M, Irizarry RA. Accounting for GC-content bias reduces systematic errors and batch effects in ChIP-seq data. Genome Res. 2017;27:1930–8. https://doi.org/10.1101/gr.220673.117.
Article
CAS
Google Scholar
Aird D, Ross MG, Chen W-S, Danielsson M, Fennell T, Russ C, et al. Analyzing and minimizing PCR amplification bias in Illumina sequencing libraries. Genome Biol. 2011;12:R18. https://doi.org/10.1186/gb-2011-12-2-r18.
Article
CAS
Google Scholar
van der Pol Y, Moldovan N, Verkuijlen S, Ramaker J, Boers D, Onstenk W, et al. The effect of preanalytical and physiological variables on cell-free DNA fragmentation. Clin Chem. 2022. https://doi.org/10.1093/clinchem/hvac029.
Markus H, Contente-Cuomo T, Farooq M, Liang WS, Borad MJ, Sivakumar S, et al. Evaluation of pre-analytical factors affecting plasma DNA analysis. Sci Rep. 2018;8:7375. https://doi.org/10.1038/s41598-018-25810-0.
Article
CAS
Google Scholar
Kerachian MA, Azghandi M, Mozaffari-Jovin S, Thierry AR. Guidelines for pre-analytical conditions for assessing the methylation of circulating cell-free DNA. Clin Epigenetics. 2021;13:193. https://doi.org/10.1186/s13148-021-01182-7.
Article
CAS
Google Scholar
Krasic J, Abramovic I, Vrtaric A, Nikolac Gabaj N, Kralik-Oguic S, Katusic Bojanac A, et al. Impact of preanalytical and analytical methods on cell-free DNA diagnostics. Front Cell Dev Biol. 2021;9:686149. https://doi.org/10.3389/fcell.2021.686149.
Article
Google Scholar
Chan KCA, Yeung S-W, Lui W-B, Rainer TH, Lo YMD. Effects of preanalytical factors on the molecular size of cell-free DNA in blood. Clin Chem. 2005;51:781–4. https://doi.org/10.1373/clinchem.2004.046219.
Article
CAS
Google Scholar
Lampignano R, Neumann MHD, Weber S, Kloten V, Herdean A, Voss T, et al. Multicenter evaluation of circulating cell-free DNA extraction and downstream analyses for the development of standardized (pre)analytical work flows. Clin Chem. 2020;66:149–60. https://doi.org/10.1373/clinchem.2019.306837.
Article
Google Scholar
Liu, Yaping. De Novo Characterization of Cell-Free DNA Fragmentation Hotspots in Plasma Whole-Genome Sequencing dbGap. Available from:
https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003062.v1.p1. 2022.
Zhou, Xionghui, Zheng Haizi, Liu, Yaping. CRAG: De novo characterization of cell-free DNA fragmentation hotspots in plasma whole-genome sequencing. Zenodo.org. Available from: https://doi.org/10.5281/zenodo.6914806
Zheng, Haizi, Liu, Yaping. CRAGR. GitHub. (2022). https://github.com/epifluidlab/cragr
Zhou, Xionghui, Liu, Yaping. CRAG. GitHub. (2022). https://github.com/epifluidlab/CRAG