{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:22:37Z","timestamp":1788481357806,"version":"build-2803163510"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2015,1,1]],"date-time":"2015-01-01T00:00:00Z","timestamp":1420070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Chronix Biomedical"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Genomic instability resulting in copy number variation is a hallmark of malignant transformation and may be identified through massive parallel sequencing. Tumor-specific cell free DNA (cfDNA) present in serum and plasma provides a real-time, easily accessible surrogate.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>DNA was extracted from serum of 204 patients with prostate cancer (Gleason score 2\u201310), 207 male controls, and patients with benign hyperplasia (n = 10) and prostatitis (n = 10). DNA was amplified by use of random primers, tagged with molecular identifiers, sequenced on a SOLID system, and aligned to the human genome. We evaluated the number of sequence reads of cfDNA in sliding 100-kbp intervals for variation from controls. We used chromosomal regions with significant variations in alignment hits for their ability to segregate patients and matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Using ROC curves to assess diagnostic performance, we evaluated the number of regions in a first subset (n = 177), with variations in alignment hits alone, provided an area under the curve (AUC) of 0.81 (95% CI 0.7\u20130.9, P &amp;lt; 0.001). Using 5 rounds of 10-fold cross-validation with the full data set, we established a final model that discriminated prostate cancer from controls with an AUC of 0.92 (0.87\u20130.95), reaching a diagnostic accuracy of 83%. Both benign prostatic hypertrophy and prostatitis could be distinguished from prostate cancer by use of cfDNA, with an accuracy of 90%.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls. This large cohort demonstrates the utility of cfDNA in prostate cancer recently established in other malignant neoplasms.<\/jats:p><\/jats:sec>","DOI":"10.1373\/clinchem.2014.226571","type":"journal-article","created":{"date-parts":[[2014,10,28]],"date-time":"2014-10-28T06:42:29Z","timestamp":1414478549000},"page":"239-248","source":"Crossref","is-referenced-by-count":41,"title":["Chromosomal Instability in Cell-Free DNA Is a Serum Biomarker for Prostate Cancer"],"prefix":"10.1093","volume":"61","author":[{"given":"Ekkehard","family":"Sch\u00fctz","sequence":"first","affiliation":[{"name":"Chronix Biomedical, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad R","family":"Akbari","sequence":"first","affiliation":[{"name":"Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada"},{"name":"Dalla Lana School of Public Health, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Beck","sequence":"first","affiliation":[{"name":"Chronix Biomedical, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Urnovitz","sequence":"first","affiliation":[{"name":"Chronix Biomedical, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Urology, Sunnybrook Research Institute, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Bornemann-Kolatzki","sequence":"first","affiliation":[{"name":"Chronix Biomedical, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M","family":"Mitchell","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K","family":"Nam","sequence":"first","affiliation":[{"name":"Division of Urology, Sunnybrook Research Institute, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A","family":"Narod","sequence":"first","affiliation":[{"name":"Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada"},{"name":"Dalla Lana School of Public Health, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,1,1]]},"reference":[{"key":"2020022605260416500_B1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.7326\/0003-4819-155-11-201112060-00375","article-title":"Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force","volume":"155","author":"Chou","year":"2011","journal-title":"Ann Intern Med"},{"key":"2020022605260416500_B2","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/0277-5379(87)90266-5","article-title":"Isolation and characterization of DNA from the plasma of cancer patients","volume":"23","author":"Stroun","year":"1987","journal-title":"Eur Cancer Clin Oncol"},{"key":"2020022605260416500_B3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.cell.2010.12.025","article-title":"Cancer genomes evolve by pulverizing single chromosomes","volume":"144","author":"Meyerson","year":"2011","journal-title":"Cell"},{"key":"2020022605260416500_B4","doi-asserted-by":"crossref","first-page":"6159","DOI":"10.1093\/nar\/gkq421","article-title":"Origin and quantification of circulating DNA in mice with human colorectal cancer xenografts","volume":"38","author":"Thierry","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2020022605260416500_B5","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1373\/clinchem.2008.113597","article-title":"Profile of the circulating DNA in apparently healthy individuals","volume":"55","author":"Beck","year":"2009","journal-title":"Clin Chem"},{"key":"2020022605260416500_B6","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1373\/clinchem.2009.123661","article-title":"Next-generation sequencing of plasma\/serum DNA: an emerging research and molecular diagnostic tool","volume":"55","author":"Lo","year":"2009","journal-title":"Clin Chem"},{"key":"2020022605260416500_B7","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1086\/301800","article-title":"Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis","volume":"62","author":"Lo","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2020022605260416500_B8","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/gm434","article-title":"Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing","volume":"5","author":"Heitzer","year":"2013","journal-title":"Genome Med"},{"key":"2020022605260416500_B9","doi-asserted-by":"crossref","first-page":"136ra68","DOI":"10.1126\/scitranslmed.3003726","article-title":"Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA","volume":"4","author":"Forshew","year":"2012","journal-title":"Sci Transl Med"},{"key":"2020022605260416500_B10","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1200\/JCO.2012.45.2011","article-title":"Liquid biopsies: genotyping circulating tumor DNA","volume":"32","author":"Diaz","year":"2014","journal-title":"J Clin Oncol"},{"key":"2020022605260416500_B11","doi-asserted-by":"crossref","first-page":"162ra154","DOI":"10.1126\/scitranslmed.3004742","article-title":"Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing","volume":"4","author":"Leary","year":"2012","journal-title":"Sci Transl Med"},{"key":"2020022605260416500_B12","doi-asserted-by":"crossref","first-page":"20ra14","DOI":"10.1126\/scitranslmed.3000702","article-title":"Development of personalized tumor biomarkers using massively parallel sequencing","volume":"2","author":"Leary","year":"2010","journal-title":"Science Trans Med"},{"key":"2020022605260416500_B13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.cca.2009.08.011","article-title":"Characterisation of circulating DNA by parallel tagged sequencing on the 454 platform","volume":"409","author":"van der Vaart","year":"2009","journal-title":"Clin Chim Acta"},{"key":"2020022605260416500_B14","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1158\/1541-7786.MCR-09-0314","article-title":"Next generation sequencing of serum circulating nucleic acids from invasive ductal breast cancer patients reveals differences to healthy and non-malignant controls","volume":"8","author":"Beck","year":"2010","journal-title":"Mol Cancer Res"},{"key":"2020022605260416500_B15","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature12065","article-title":"Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA","volume":"497","author":"Murtaza","year":"2013","journal-title":"Nature"},{"key":"2020022605260416500_B16","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1002\/gcc.20815","article-title":"Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors","volume":"49","author":"McBride","year":"2010","journal-title":"Genes Chromosomes Cancer"},{"key":"2020022605260416500_B17","first-page":"368","article-title":"Analysis of circulating tumor DNA to monitor metastatic breast cancer","volume":"28","author":"Dawson","year":"2013","journal-title":"N Engl J Med"},{"key":"2020022605260416500_B18","doi-asserted-by":"crossref","first-page":"224ra24","DOI":"10.1126\/scitranslmed.3007094","article-title":"Detection of circulating tumor DNA in early- and late-stage human malignancies","volume":"6","author":"Bettegowda","year":"2014","journal-title":"Sci Transl Med"},{"key":"2020022605260416500_B19","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nm.3519","article-title":"An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage","volume":"20","author":"Newman","year":"2014","journal-title":"Nat Med"},{"key":"2020022605260416500_B20","first-page":"8","article-title":"Genome aberrations in canine mammary carcinomas and their detection in cell-free plasma DNA","volume":"30","author":"Beck","year":"2013","journal-title":"PLoS One"},{"key":"2020022605260416500_B21","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1373\/clinchem.2012.196014","article-title":"Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing","volume":"59","author":"Chan","year":"2013","journal-title":"Clin Chem"},{"key":"2020022605260416500_B22","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/B978-1-4377-0792-2.50012-2","article-title":"Neoplasia","volume-title":"Robbins and Cotran pathologic basis of disease","author":"Sticker","year":"2010","edition":"8th Ed"},{"key":"2020022605260416500_B23","unstructured":"Mitelman F , JohanssonB, MertensF, Eds. Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. http:\/\/cgap.nci.nih.gov\/Chromosomes\/Mitelman (Accessed October 2014)."},{"key":"2020022605260416500_B24","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.4161\/cc.10.13.16352","article-title":"Is carcinogenesis a form of speciation?","volume":"10","author":"Duesberg","year":"2011","journal-title":"Cell Cycle"},{"key":"2020022605260416500_B25","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4161\/cc.11.6.19580","article-title":"Origin of metastases: subspecies of cancers generated by intrinsic karyotypic variations","volume":"11","author":"Duesberg","year":"2012","journal-title":"Cell Cycle"},{"key":"2020022605260416500_B26","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature09744","article-title":"The genomic complexity of primary human prostate cancer","volume":"470","author":"Berger","year":"2011","journal-title":"Nature"},{"key":"2020022605260416500_B27","first-page":"241","article-title":"Les acides nucl\u00e9iques du plasma sanguin chez l'homme","volume":"142","author":"Mandel","year":"1948","journal-title":"C R Seances Soc Biol Fil"},{"key":"2020022605260416500_B28","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/sj.bjc.6601609","article-title":"Quantitation of circulating DNA in the serum of breast cancer patients by real-time PCR","volume":"90","author":"Gal","year":"2004","journal-title":"Br J Cancer"},{"key":"2020022605260416500_B29","first-page":"3761","article-title":"Tumor DNA in plasma at diagnosis of breast cancer patients is a valuable predictor of disease-free survival","volume":"8","author":"Silva","year":"2002","journal-title":"Clin Cancer Res"},{"key":"2020022605260416500_B30","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1200\/JCO.2003.02.006","article-title":"Quantification of free circulating DNA as a diagnostic marker in lung cancer","volume":"21","author":"Sozzi","year":"2003","journal-title":"J Clin Oncol"},{"key":"2020022605260416500_B31","doi-asserted-by":"crossref","first-page":"19920","DOI":"10.1073\/pnas.0810373105","article-title":"Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma","volume":"105","author":"Lun","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020022605260416500_B32","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/gim.2011.73","article-title":"DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study","volume":"14","author":"Palomaki","year":"2012","journal-title":"Genet Med"},{"key":"2020022605260416500_B33","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/j.1863-2378.2009.01260.x","article-title":"Serum nucleic acids in an experimental bovine transmissible spongiform encephalopathy model","volume":"56","author":"Beck","year":"2009","journal-title":"Zoonoses Public Health"},{"key":"2020022605260416500_B34","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1093\/nar\/gkn963","article-title":"Disease-specific motifs can be identified in circulating nucleic acids from live elk and cattle infected with transmissible spongiform encephalopathies","volume":"37","author":"Gordon","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"2020022605260416500_B35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.2353\/jmoldx.2010.090170","article-title":"Serum DNA motifs predict disease and clinical status in multiple sclerosis","volume":"12","author":"Beck","year":"2010","journal-title":"J Mol Diagn"},{"key":"2020022605260416500_B36","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2013.31.15_suppl.11013","article-title":"Cell-free DNA copy number variations as a marker for breast cancer in a large study cohort [Abstract]","volume":"31","author":"Beck","year":"2013","journal-title":"J Clin Oncol"},{"key":"2020022605260416500_B37","doi-asserted-by":"crossref","first-page":"e1004271","DOI":"10.1371\/journal.pgen.1004271","article-title":"Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing","volume":"10","author":"Mohan","year":"2014","journal-title":"PLoS Genet"},{"key":"2020022605260416500_B38","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2014.32.15_suppl.6072","article-title":"Detection of novel HPV mutations and chromosomal number imbalance (CNI) in laryngeal cancer using next-generation sequencing (NGS) [Abstract]","volume":"32","author":"Urnovitz","year":"2014","journal-title":"J Clin Oncol"},{"key":"2020022605260416500_B39","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2014.32.15_suppl.e14549","article-title":"Comprehensive analyses of rectal cancer genomes to reveal copy number variations as potential predictor of induction therapy efficacy [Abstract]","volume":"32","author":"Beck","year":"2014","journal-title":"J Clin Oncol"}],"container-title":["Clinical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/61\/1\/239\/32640461\/clinchem0239.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/61\/1\/239\/32640461\/clinchem0239.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T05:28:13Z","timestamp":1598419693000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/clinchem\/article\/61\/1\/239\/5611433"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,1]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,1,1]]},"published-print":{"date-parts":[[2015,1,1]]}},"URL":"https:\/\/doi.org\/10.1373\/clinchem.2014.226571","relation":{},"ISSN":["0009-9147","1530-8561"],"issn-type":[{"value":"0009-9147","type":"print"},{"value":"1530-8561","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,1,1]]},"published":{"date-parts":[[2015,1,1]]}}}