{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:59:36Z","timestamp":1792195176767,"version":"4.4.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31471299"],"award-info":[{"award-number":["31471299"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81522046"],"award-info":[{"award-number":["81522046"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81800195"],"award-info":[{"award-number":["81800195"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Epigenet"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy. To investigate the correlation between 5hmC modifications and curative effectiveness, we separated patients into training (<jats:italic>n<\/jats:italic>\u2009=\u200956) and validation (<jats:italic>n<\/jats:italic>\u2009=\u200930) cohorts and developed a 5hmC-based logistic regression model from the training cohort to predict the treatment response in the validation cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we identified thirteen 5hmC markers associated with treatment response. The prediction performance of the logistic regression model, achieving 0.82 sensitivity and 0.75 specificity (AUC\u2009=\u20090.78), was superior to existing clinical indicators, such as LDH and stage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest that the 5hmC modifications in cfDNA at the time before R-CHOP treatment are associated with treatment response and that 5hmC-Seal may potentially serve as a clinical-applicable, minimally invasive approach to predict R-CHOP treatment response for DLBCL patients.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13148-020-00973-8","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T17:04:01Z","timestamp":1613063041000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients"],"prefix":"10.1186","volume":"13","author":[{"given":"Hang-Yu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Long","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Ruo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjian","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu-Bing","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Chuan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1519-9679","authenticated-orcid":false,"given":"Jian","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Mei","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"973_CR1","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","volume":"32","author":"BD Cheson","year":"2014","unstructured":"Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classifification. J Clin Oncol. 2014;32:3059\u201367.","journal-title":"J Clin Oncol"},{"issue":"10","key":"973_CR2","doi-asserted-by":"publisher","first-page":"4047","DOI":"10.1182\/blood-2005-10-4213","volume":"107","author":"I Oschlies","year":"2006","unstructured":"Oschlies I, et al. Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin\u2013Frankfurt\u2013Munster) Multicenter Trial. Blood. 2006a;107(10):4047\u201352.","journal-title":"Blood"},{"issue":"28","key":"973_CR3","doi-asserted-by":"publisher","first-page":"4587","DOI":"10.1200\/JCO.2007.15.9277","volume":"26","author":"K Fu","year":"2008","unstructured":"Fu K, et al. Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. J Clin Oncol. 2008;26(28):4587\u201394.","journal-title":"J Clin Oncol"},{"key":"973_CR4","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1182\/asheducation-2016.1.366","volume":"1","author":"B Coiffier","year":"2016","unstructured":"Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure\u2014what to do? American Society of Hematology. 2016;1:366\u201378.","journal-title":"American Society of Hematology"},{"issue":"10","key":"973_CR5","doi-asserted-by":"publisher","first-page":"4047","DOI":"10.1182\/blood-2005-10-4213","volume":"107","author":"I Oschlies","year":"2006","unstructured":"Oschlies I, et al. Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin\u2013Frankfurt\u2013M\u00fcnster) Multicenter Trial. Blood. 2006b;107(10):4047\u201352.","journal-title":"Blood"},{"key":"973_CR6","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.leukres.2018.07.014","volume":"71","author":"SH Kim","year":"2018","unstructured":"Kim SH, et al. Prognostic impact of pretreatment albumin to globulin ratio in patients with diffuse large B-cell lymphoma treated with R-CHOP. Leuk Res. 2018;71:100\u20135.","journal-title":"Leuk Res"},{"issue":"3","key":"973_CR7","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s11899-016-0318-1","volume":"11","author":"SF Barrington","year":"2016","unstructured":"Barrington SF, Mikhaeel NG. PET scans for staging and restaging in diffuse large B-cell and follicular lymphomas. Curr Hematologic Malig Rep. 2016;11(3):185\u201395.","journal-title":"Curr Hematologic Malig Rep"},{"issue":"14","key":"973_CR8","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJM199309303291402","volume":"329","author":"International Non-Hodgkin's Lymphoma Prognostic Factors Project","year":"1993","unstructured":"International Non-Hodgkin\u2019s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin\u2019s lymphoma. N Engl J Med. 1993;329(14):987\u201394.","journal-title":"N Engl J Med"},{"issue":"6","key":"973_CR9","first-page":"393","volume":"60","author":"CR Flowers","year":"2010","unstructured":"Flowers CR, Sinha R, Vose JM. Improving outcomes for patients with diffuse large B-cell lymphoma. CA Cancer J Clin. 2010;60(6):393\u2013408.","journal-title":"CA Cancer J Clin"},{"issue":"6","key":"973_CR10","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1182\/blood-2013-09-524108","volume":"123","author":"Z Zhou","year":"2014","unstructured":"Zhou Z, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837\u201342.","journal-title":"Blood"},{"issue":"9","key":"973_CR11","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.7150\/jca.29807","volume":"10","author":"Y Deng","year":"2019","unstructured":"Deng Y, et al. EZH2\/Bcl-2 coexpression predicts worse survival in diffuse large B-cell lymphomas and demonstrates poor efficacy to rituximab in localized lesions. J Cancer. 2019;10(9):2006\u201317.","journal-title":"J Cancer"},{"issue":"5","key":"973_CR12","doi-asserted-by":"publisher","first-page":"3515","DOI":"10.1007\/s12032-012-0232-x","volume":"29","author":"O Markovic","year":"2012","unstructured":"Markovic O, et al. Survivin expression in patients with newly diagnosed nodal diffuse large B cell lymphoma (DLBCL). Med Oncol. 2012;29(5):3515\u201321.","journal-title":"Med Oncol"},{"issue":"9","key":"973_CR13","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1080\/10428194.2017.1410884","volume":"59","author":"H Arima","year":"2018","unstructured":"Arima H, et al. Prognostic impact of activation-induced cytidine deaminase expression for patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2018;59(9):2085\u201395.","journal-title":"Leuk Lymphoma"},{"issue":"10","key":"973_CR14","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1007\/s00277-014-2111-3","volume":"93","author":"G Song","year":"2014","unstructured":"Song G, et al. Serum microRNA expression profiling predict response to R-CHOP treatment in diffuse large B cell lymphoma patients. Ann Hematol. 2014;93(10):1735\u201343.","journal-title":"Ann Hematol"},{"issue":"1","key":"973_CR15","doi-asserted-by":"publisher","first-page":"35","DOI":"10.2217\/epi-2018-0123","volume":"11","author":"Y Feng","year":"2019","unstructured":"Feng Y, et al. Exosome-derived miRNAs as predictive biomarkers for diffuse large B-cell lymphoma chemotherapy resistance. Epigenomics. 2019;11(1):35\u201351.","journal-title":"Epigenomics"},{"issue":"1","key":"973_CR16","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/1756-8722-5-51","volume":"5","author":"X Jin","year":"2012","unstructured":"Jin X, et al. Homozygous A polymorphism of the complement C1qA276correlates with prolonged overall survival in patients with diffuse large B cell lymphoma treated with R-CHOP. J Hematol Oncol. 2012;5(1):51.","journal-title":"J Hematol Oncol"},{"issue":"8","key":"973_CR17","doi-asserted-by":"publisher","first-page":"2720","DOI":"10.1182\/blood-2006-01-009480","volume":"108","author":"DH Kim","year":"2006","unstructured":"Kim DH, et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood. 2006;108(8):2720\u20135.","journal-title":"Blood"},{"issue":"3","key":"973_CR18","doi-asserted-by":"publisher","first-page":"363","DOI":"10.3324\/haematol.2014.110189","volume":"100","author":"R Coutinho","year":"2015","unstructured":"Coutinho R, et al. Revisiting the immune microenvironment of diffuse large B-cell lymphoma using a tissue microarray and immunohistochemistry: robust semi-automated analysis reveals CD3 and FoxP3 as potential predictors of response to R-CHOP. Haematologica. 2015;100(3):363\u20139.","journal-title":"Haematologica"},{"key":"973_CR19","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/nrc3066","volume":"11","author":"H Schwarzenbach","year":"2011","unstructured":"Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426\u201337.","journal-title":"Nat Rev Cancer"},{"issue":"11\u201312","key":"973_CR20","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.cca.2011.02.013","volume":"412","author":"C Dahl","year":"2011","unstructured":"Dahl C, Gronbaek K, Guldberg P. Advances in DNA methylation:5-hydroxymethylcytosine revisited. Clin Chim Acta. 2011;412(11\u201312):831\u20136.","journal-title":"Clin Chim Acta"},{"issue":"1","key":"973_CR21","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s13148-016-0261-y","volume":"8","author":"LS Kristensen","year":"2016","unstructured":"Kristensen LS, et al. Aberrant methylation of cell-free circulating DNA in plasma predicts poor outcome in diffuse large B cell lymphoma. Clin Epigenetics. 2016;8(1):95\u201395.","journal-title":"Clin Epigenetics"},{"key":"973_CR22","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1126\/science.1170116","volume":"324","author":"M Tahiliani","year":"2009","unstructured":"Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930\u20135.","journal-title":"Science"},{"key":"973_CR23","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1126\/science.1169786","volume":"324","author":"S Kriaucionis","year":"2009","unstructured":"Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324:929\u201330.","journal-title":"Science"},{"key":"973_CR24","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.cbpa.2012.10.002","volume":"16","author":"Y Fu","year":"2012","unstructured":"Fu Y, He C. Nucleic acid modififications with epigenetic signifificance. Curr Opin Chem Biol. 2012;16:516\u201324.","journal-title":"Curr Opin Chem Biol"},{"key":"973_CR25","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nrg3080","volume":"13","author":"MR Branco","year":"2011","unstructured":"Branco MR, Ficz G, Reik W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet. 2011;13:7\u201313.","journal-title":"Nat Rev Genet"},{"issue":"19","key":"973_CR26","doi-asserted-by":"publisher","first-page":"2790","DOI":"10.1182\/bloodadvances.2019000175","volume":"3","author":"BCH Chiu","year":"2019","unstructured":"Chiu BCH, et al. Prognostic implications of 5-hydroxymethylcytosines from circulating cell-free DNA in diffuse large B-cell lymphoma. Blood Adv. 2019;3(19):2790\u20139.","journal-title":"Blood Adv"},{"key":"973_CR27","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1007\/s00277-010-0990-5","volume":"89","author":"C Fang","year":"2010","unstructured":"Fang C, Xu W, et al. A systematic review and meta-analysis of rituximab-based immunochemotherapy for subtypes of diffuse large B cell lymphoma. Ann Hematol. 2010;89:1107\u201313.","journal-title":"Ann Hematol"},{"issue":"11","key":"973_CR28","first-page":"1719","volume":"2017","author":"RL Van Heertum","year":"2014","unstructured":"Van Heertum RL, Scarimbolo R, et al. Lugano 2014 criteria for assessing FDG-PET\/ CT in lymphoma: an operational approach for clinical trials. Drug Des Dev Therapy. 2014;2017(11):1719\u201328.","journal-title":"Drug Des Dev Therapy"},{"key":"973_CR29","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nbt.1732","volume":"29","author":"CX Song","year":"2011","unstructured":"Song CX, Szulwach KE, Fu Y, et al. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol. 2011;29:68\u201372.","journal-title":"Nat Biotechnol"},{"key":"973_CR30","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","volume":"9","author":"B Langmead","year":"2012","unstructured":"Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357\u20139.","journal-title":"Nat Methods"},{"issue":"9","key":"973_CR31","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/gb-2008-9-9-r137","volume":"9","author":"Y Zhang","year":"2008","unstructured":"Zhang Y, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):137.","journal-title":"Genome Biol"},{"key":"973_CR32","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","volume":"26","author":"AR Quinlan","year":"2010","unstructured":"Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841\u20132.","journal-title":"Bioinformatics"},{"key":"973_CR33","doi-asserted-by":"publisher","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","volume":"9","author":"Y Zhang","year":"2008","unstructured":"Zhang Y, Liu T, Meyer CA, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.","journal-title":"Genome Biol"},{"key":"973_CR34","first-page":"2825","volume":"12","author":"F Pedregosa","year":"2011","unstructured":"Pedregosa F, Varoquaux G, Gramfort A, Michel V, Thirion B, Grisel O, et al. Scikit-learn: machine learning in Python. J Mach Learn Res. 2011;12:2825\u201330.","journal-title":"J Mach Learn Res"},{"issue":"10","key":"973_CR35","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/nar\/gks042","volume":"40","author":"DJ McCarthy","year":"2012","unstructured":"McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40(10):4288\u201397.","journal-title":"Nucleic Acids Res"},{"issue":"14","key":"973_CR36","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1093\/bioinformatics\/btv145","volume":"31","author":"G Yu","year":"2015","unstructured":"Yu G, Wang LG, He QY. ChIPseeker: an R\/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics. 2015;31(14):2382\u20133.","journal-title":"Bioinformatics"},{"issue":"15","key":"973_CR37","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1056\/NEJMoa1801445","volume":"378","author":"R Schmitz","year":"2018","unstructured":"Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396\u2013407.","journal-title":"N Engl J Med"},{"key":"973_CR38","doi-asserted-by":"crossref","unstructured":"Goldman M, Craft B, Brooks A, Zhu J, Haussler D. The UCSC Xena Platform for cancer genomics data visualization and interpretation. BioRxiv 2018; 326470.","DOI":"10.1101\/326470"},{"key":"973_CR39","unstructured":"Hothorn T, Hothorn MT, Suggests TH. Package \u2018maxstat\u2019. 2017."},{"issue":"4","key":"973_CR40","doi-asserted-by":"publisher","first-page":"274","DOI":"10.4103\/0974-7788.76794","volume":"1","author":"MK Goel","year":"2010","unstructured":"Goel MK, Khanna P, Kishore J. Understanding survival analysis: Kaplan\u2013Meier estimate. Int J Ayurveda Res. 2010;1(4):274.","journal-title":"Int J Ayurveda Res"},{"key":"973_CR41","first-page":"41","volume-title":"Estimation of survival probabilities. Analysing survival data from clinical trials and observational studies","author":"E Marubini","year":"1995","unstructured":"Marubini E, Valsecchi MG. Estimation of survival probabilities. Analysing survival data from clinical trials and observational studies. Chichester: Wiley; 1995. p. 41\u20138."},{"issue":"21","key":"973_CR42","doi-asserted-by":"publisher","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","volume":"77","author":"T Li","year":"2017","unstructured":"Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B, Liu XS. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77(21):e108\u201310.","journal-title":"Cancer Res"},{"key":"973_CR43","doi-asserted-by":"crossref","unstructured":"McKight PE, Najab J. Kruskal\u2013Wallis test. The Corsini Encyclopedia of Psychology 2010;1-1.","DOI":"10.1002\/9780470479216.corpsy0491"},{"key":"973_CR44","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1214\/aoms\/1177729380","volume":"23","author":"WG Cochran","year":"1952","unstructured":"Cochran WG. The \u03c72 test of goodness of fit. Ann Math Stat. 1952;23:315\u201345.","journal-title":"Ann Math Stat"},{"key":"973_CR45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00402","volume":"3","author":"MA Applebaum","year":"2019","unstructured":"Applebaum MA, Barr EK, et al. 5-Hydroxymethylcytosine profifiles are prognostic of outcome in neuroblastoma and reveal transcriptional networks that correlate with tumor phenotype. JCO Precis Oncol. 2019;3:1\u201312.","journal-title":"JCO Precis Oncol"},{"key":"973_CR46","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.gpb.2018.06.002","volume":"16","author":"Ji Zhang","year":"2018","unstructured":"Zhang Ji, Han X, et al. 5-hydroxymethylome in circulating cell-free DNA as A potential biomarker for non-small-cell lung cancer. Genomics Proteomics Bioinformatics. 2018;16:187\u201399.","journal-title":"Genomics Proteomics Bioinformatics"},{"issue":"11","key":"973_CR47","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/nm.3394","volume":"19","author":"DF Quail","year":"2013","unstructured":"Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423\u201337.","journal-title":"Nat Med"},{"key":"973_CR48","first-page":"8586354","volume":"2019","author":"IC Alexandra","year":"2019","unstructured":"Alexandra IC, Patricia IS, Liana S, et al. Tumor microenvironment in diffuse large B-cell lymphoma: role and prognosis. Anal Cell Pathol. 2019;2019:8586354.","journal-title":"Anal Cell Pathol"},{"key":"973_CR49","doi-asserted-by":"publisher","first-page":"840","DOI":"10.3390\/ijms20040840","volume":"20","author":"RR Catarina","year":"2019","unstructured":"Catarina RR, Rita M. Targeting tumor microenvironment for cancer therapy. Int J Mol Sci. 2019;20:840.","journal-title":"Int J Mol Sci"},{"issue":"10","key":"973_CR50","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1038\/cr.2017.106","volume":"27","author":"C-X Song","year":"2017","unstructured":"Song C-X, et al. 5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages. Cell Res. 2017;27(10):1231\u201342.","journal-title":"Cell Res"},{"key":"973_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1368.001","volume":"1075","author":"R Swaminathan","year":"2006","unstructured":"Swaminathan R, Butt AN. Circulating nucleic acids in plasma and serum: recent developments. Ann N Y Acad Sci. 2006;1075:1\u20139.","journal-title":"Ann N Y Acad Sci"},{"key":"973_CR52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/erm.2014.24","volume":"17","author":"T Venessa","year":"2015","unstructured":"Venessa T, Adnan M, et al. Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities. Expert Rev Mol Med. 2015;17:1\u201314.","journal-title":"Expert Rev Mol Med"},{"issue":"4","key":"973_CR53","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41556-020-0488-x","volume":"22","author":"PM M\u00fcller","year":"2020","unstructured":"M\u00fcller PM, Rademacher J, Bagshaw RD, et al. Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nat Cell Biol. 2020;22(4):498\u2013511.","journal-title":"Nat Cell Biol"},{"issue":"36","key":"973_CR54","doi-asserted-by":"publisher","first-page":"26483","DOI":"10.1074\/jbc.M604376200","volume":"281","author":"K Patrick","year":"2006","unstructured":"Patrick K, Stemmle LN, Madden JF, et al. A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem. 2006;281(36):26483\u201390.","journal-title":"J Biol Chem"},{"issue":"21","key":"973_CR55","doi-asserted-by":"publisher","first-page":"8173","DOI":"10.1073\/pnas.0510254103","volume":"103","author":"P Kelly","year":"2006","unstructured":"Kelly P, et al. The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. PNAS. 2006;103(21):8173\u20138.","journal-title":"PNAS"},{"issue":"4","key":"973_CR56","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1016\/j.bbrc.2016.04.048","volume":"473","author":"Bo Yuan","year":"2016","unstructured":"Yuan Bo, et al. G\u03b112\/13 signaling promotes cervical cancer invasion through the RhoA\/ROCK-JNK signaling axis. Biochem Biophys Res Commun. 2016;473(4):1240\u20136.","journal-title":"Biochem Biophys Res Commun"},{"key":"973_CR57","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1038\/s41388-017-0038-6","volume":"37","author":"A Suhail","year":"2018","unstructured":"Suhail A, Hui Sun L, et al. GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers. Oncogene. 2018;37:1340\u201353.","journal-title":"Oncogene"},{"key":"973_CR58","doi-asserted-by":"publisher","first-page":"ra60","DOI":"10.1126\/scisignal.2002221","volume":"4","author":"H Yagi","year":"2011","unstructured":"Yagi H, et al. A synthetic biology approach reveals a CXCR4\u2013G13\u2013Rho signaling axis driving transendothelial migration of metastatic breast cancer cells. Sci Signal. 2011;4:ra60.","journal-title":"Sci Signal"},{"key":"973_CR59","doi-asserted-by":"publisher","first-page":"4514","DOI":"10.1242\/jcs.132381","volume":"126","author":"AP Struckhof","year":"2013","unstructured":"Struckhof AP, et al. PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA. J Cell Sci. 2013;126:4514\u201326.","journal-title":"J Cell Sci"}],"container-title":["Clinical Epigenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-020-00973-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13148-020-00973-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-020-00973-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T01:54:08Z","timestamp":1724464448000},"score":1,"resource":{"primary":{"URL":"https:\/\/clinicalepigeneticsjournal.biomedcentral.com\/articles\/10.1186\/s13148-020-00973-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,11]]},"references-count":59,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["973"],"URL":"https:\/\/doi.org\/10.1186\/s13148-020-00973-8","relation":{},"ISSN":["1868-7075","1868-7083"],"issn-type":[{"value":"1868-7075","type":"print"},{"value":"1868-7083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,11]]},"assertion":[{"value":"22 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study was conducted according to the guidelines of the Helsinki Declaration and was approved by the Ethics Committee of Peking University Third Hospital. Written informed consent was obtained from all participants.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no conflict of interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"33"}}