{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T20:24:46Z","timestamp":1776803086949,"version":"3.51.2"},"reference-count":40,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nyckelfonden-\u00d6rebro University Hospital Research Foundation"},{"name":"Lions Fund for Cancer Research Uppsala-\u00d6rebro"},{"name":"Uppsala-\u00d6rebro Regional Research Council"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We aimed to investigate the use of free glycosaminoglycan profiles (GAGomes) and cfDNA in plasma to differentiate between lung cancer and benign lung disease, in a cohort of 113 patients initially suspected of lung cancer. GAGomes were analyzed in all samples using the MIRAM\u00ae Free Glycosaminoglycan Kit with ultra-high-performance liquid chromatography and electrospray ionization triple quadrupole mass spectrometry. In a subset of samples, cfDNA concentration and NGS-data was available. We detected two GAGome features, 0S chondroitin sulfate (CS), and 4S CS, with cancer-specific changes. Based on the observed GAGome changes, we devised a model to predict lung cancer. The model, named the GAGome score, could detect lung cancer with 41.2% sensitivity (95% CI: 9.2\u201354.2%) at 96.4% specificity (95% CI: 95.2\u2013100.0%, n = 113). When we combined the GAGome score with a cfDNA-based model, the sensitivity increased from 42.6% (95% CI: 31.7\u201360.6%, cfDNA alone) to 70.5% (95% CI: 57.4\u201381.5%) at 95% specificity (95% CI: 75.1\u2013100%, n = 74). Notably, the combined GAGome and cfDNA testing improved the sensitivity, compared to cfDNA alone, especially in ASCL stage I (55.6% vs 11.1%). Our findings show that plasma GAGome profiles can enhance cfDNA testing performance, highlighting the applicability of a multiomics approach in lung cancer diagnostics.<\/jats:p>","DOI":"10.3390\/ijms25189777","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T05:53:03Z","timestamp":1725947583000},"page":"9777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discriminating Benign from Malignant Lung Diseases Using Plasma Glycosaminoglycans and Cell-Free DNA"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-947X","authenticated-orcid":false,"given":"Alvida","family":"Qvick","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine and Health, \u00d6rebro University, 701 82 \u00d6rebro, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1663-2227","authenticated-orcid":false,"given":"Sinisa","family":"Bratulic","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8457-7592","authenticated-orcid":false,"given":"Jessica","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine and Health, \u00d6rebro University, 701 82 \u00d6rebro, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4637-8626","authenticated-orcid":false,"given":"Bianca","family":"Stenmark","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine and Health, \u00d6rebro University, 701 82 \u00d6rebro, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4669-1367","authenticated-orcid":false,"given":"Christina","family":"Karlsson","sequence":"additional","affiliation":[{"name":"School of Health Sciences, \u00d6rebro University, 701 82 \u00d6rebro, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-6003","authenticated-orcid":false,"given":"Jens","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden"},{"name":"BioInnovation Institute, Ole Maal\u00f8es Vej 3, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-9562","authenticated-orcid":false,"given":"Francesco","family":"Gatto","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden"},{"name":"Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2317-5738","authenticated-orcid":false,"given":"Gisela","family":"Helenius","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine and Health, \u00d6rebro University, 701 82 \u00d6rebro, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"587","DOI":"10.2217\/bmm-2018-0093","article-title":"Circulating cell-free DNA as a diagnostic and prognostic biomarker for non-small-cell lung cancer: A systematic review and meta-analysis","volume":"14","author":"Chen","year":"2020","journal-title":"Biomark. Med."},{"key":"ref_2","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":"ref_3","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1126\/science.aar3247","article-title":"Detection and localization of surgically resectable cancers with a multi-analyte blood test","volume":"359","author":"Cohen","year":"2018","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eabp8704","DOI":"10.1126\/scitranslmed.abp8704","article-title":"Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection","volume":"14","author":"Wang","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41416-022-01768-9","article-title":"Circulating tumour cells in the -omics era: How far are we from achieving the \u2018singularity\u2019?","volume":"127","author":"Visal","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12943-021-01323-9","article-title":"Non-invasive lung cancer diagnosis and prognosis based on multi-analyte liquid biopsy","volume":"20","author":"Chen","year":"2021","journal-title":"Mol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tomeva, E., Switzeny, O.J., Heitzinger, C., Hippe, B., and Haslberger, A.G. (2022). Comprehensive Approach to Distinguish Patients with Solid Tumors from Healthy Controls by Combining Androgen Receptor Mutation p.H875Y with Cell-Free DNA Methylation and Circulating miRNAs. Cancers, 14.","DOI":"10.3390\/cancers14020462"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1146\/annurev-biodatasci-122120-113218","article-title":"Extracellular Vesicle\u2013Based Multianalyte Liquid Biopsy as a Diagnostic for Cancer","volume":"5","author":"Lin","year":"2022","journal-title":"Annu. Rev. Biomed. Data Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1039\/c2mb25021g","article-title":"Proteoglycan sequence","volume":"8","author":"Li","year":"2012","journal-title":"Mol. BioSyst."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev.cellbio.22.010605.093433","article-title":"The Molecular Diversity of Glycosaminoglycans Shapes Animal Development","volume":"22","author":"Hobert","year":"2006","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/iep.12428","article-title":"Role of extracellular matrix proteoglycans in immune cell recruitment","volume":"103","author":"Gray","year":"2022","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1111\/j.1582-4934.2009.00826.x","article-title":"Immunomodulatory and anti-inflammatory effects of chondroitin sulphate","volume":"13","author":"Montell","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.matbio.2015.02.003","article-title":"Proteoglycan form and function: A comprehensive nomenclature of proteoglycans","volume":"42","author":"Iozzo","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1002\/pmic.200700176","article-title":"Proteoglycanomics: Tools to unravel the biological function of glycosaminoglycans","volume":"7","author":"Gesslbauer","year":"2007","journal-title":"Proteomics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1089\/omi.2011.0102","article-title":"A Structural Analysis of Glycosaminoglycans from Lethal and Nonlethal Breast Cancer Tissues: Toward a Novel Class of Theragnostics for Personalized Medicine in Oncology?","volume":"16","author":"Weyers","year":"2012","journal-title":"OMICS"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2200361","DOI":"10.1200\/PO.22.00361","article-title":"Plasma and Urine Free Glycosaminoglycans as Monitoring and Predictive Biomarkers in Metastatic Renal Cell Carcinoma: A Prospective Cohort Study","volume":"7","author":"Gatto","year":"2023","journal-title":"JCO Precis. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.euros.2022.06.003","article-title":"Plasma and Urine Free Glycosaminoglycans as Monitoring Biomarkers in Nonmetastatic Renal Cell Carcinoma\u2014A Prospective Cohort Study","volume":"42","author":"Gatto","year":"2022","journal-title":"Eur. Urol. Open Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4760","DOI":"10.1038\/s41467-022-32530-7","article-title":"Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S1357-2725(02)00264-9","article-title":"Altered content composition and structure of glycosaminoglycans and proteoglycans in gastric carcinoma","volume":"35","author":"Theocharis","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Balbisi, M., Sug\u00e1r, S., Schlosser, G., Szeitz, B., Fillinger, J., Moldvay, J., Drahos, L., Sz\u00e1sz, A.M., T\u00f3th, G., and Turi\u00e1k, L. (2023). Inter- and intratumoral proteomics and glycosaminoglycan characterization of ALK rearranged lung adenocarcinoma tissues: A pilot study. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-33435-1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s10719-017-9790-7","article-title":"Glycosaminoglycans and glycolipids as potential biomarkers in lung cancer","volume":"34","author":"Li","year":"2017","journal-title":"Glycoconj. J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"P\u00e1l, D., T\u00f3th, G., Sug\u00e1r, S., F\u00fcgedi, K.D., Szab\u00f3, D., Kovalszky, I., Papp, D., Schlosser, G., T\u00f3th, C., and Torn\u00f3czky, T. (2023). Compositional Analysis of Glycosaminoglycans in Different Lung Cancer Types\u2014A Pilot Study. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087050"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1158\/2159-8290.CD-21-1252","article-title":"The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer","volume":"13","author":"Mattox","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2115328119","DOI":"10.1073\/pnas.2115328119","article-title":"Noninvasive detection of any-stage cancer using free glycosaminoglycans","volume":"119","author":"Bratulic","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1515\/cclm-2023-0541","article-title":"Ultra-short cell-free DNA fragments enhance cancer early detection in a multi-analyte blood test combining mutation, protein and fragmentomics","volume":"62","author":"Wang","year":"2023","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"D\u2019Ambrosi, S., Giannoukakos, S., Antunes-Ferreira, M., Pedraz-Valdunciel, C., Bracht, J.W., Potie, N., Gimenez-Capitan, A., Hackenberg, M., Fernandez Hilario, A., and Molina-Vila, M.A. (2023). Combinatorial Blood Platelets-Derived circRNA and mRNA Signature for Early-Stage Lung Cancer Detection. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054881"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bratulic, S., Limeta, A., Maccari, F., Galeotti, F., Volpi, N., Levin, M., Nielsen, J., and Gatto, F. (2022). Analysis of normal levels of free glycosaminoglycans in urine and plasma in adults. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101575"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1590\/s1677-5538.ibju.2017.0569","article-title":"Prospective Evaluation of Chondroitin Sulfate, Heparan Sulfate and Hyaluronic Acid in Prostate Cancer","volume":"44","author":"Mendes","year":"2018","journal-title":"Int. Braz. J. Urol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.bbagen.2006.10.015","article-title":"Analysis of plasma proteins that bind to glycosaminoglycans","volume":"1770","author":"Saito","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S1054-3589(05)53005-9","article-title":"The biosynthesis and catabolism of galactosaminoglycans","volume":"53","author":"Prabhakar","year":"2006","journal-title":"Adv. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e012799","DOI":"10.1136\/bmjopen-2016-012799","article-title":"STARD 2015 guidelines for reporting diagnostic accuracy studies: Explanation and elaboration","volume":"6","author":"Cohen","year":"2016","journal-title":"BMJ Open"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.chest.2016.10.010","article-title":"The Eighth Edition Lung Cancer Stage Classification","volume":"151","author":"Detterbeck","year":"2017","journal-title":"Chest"},{"key":"ref_33","unstructured":"Travis, W.D., Brambilla, E., M\u00fcller-Hermelink, H.K., and Harris, C.C. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart, IARC Press."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"122761","DOI":"10.1016\/j.jchromb.2021.122761","article-title":"Analytical performance of a standardized kit for mass spectrometry-based measurements of human glycosaminoglycans","volume":"1177","author":"Tamburro","year":"2021","journal-title":"J. Chromatogr. B"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nprot.2014.026","article-title":"Analysis of glycosaminoglycan-derived, precolumn, 2-aminoacridone\u2013labeled disaccharides with LC-fluorescence and LC-MS detection","volume":"9","author":"Volpi","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s10020-021-00331-1","article-title":"Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer","volume":"27","author":"Qvick","year":"2021","journal-title":"Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1037\/a0029146","article-title":"Bayesian estimation supersedes the t test","volume":"142","author":"Kruschke","year":"2013","journal-title":"J. Exp. Psychol. Gen."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1214\/20-BA1221","article-title":"Rank-Normalization, Folding, and Localization: An Improved R^ for Assessing Convergence of MCMC (with Discussion)","volume":"16","author":"Vehtari","year":"2021","journal-title":"Bayesian Anal."},{"key":"ref_39","first-page":"1","article-title":"brms: An R Package for Bayesian Multilevel Models Using Stan","volume":"80","year":"2017","journal-title":"J. Stat. Softw."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.21105\/joss.01541","article-title":"bayestestR: Describing Effects and their Uncertainty, Existence and Significance within the Bayesian Framework","volume":"4","author":"Makowski","year":"2019","journal-title":"J. Open Source Softw."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9777\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:52:50Z","timestamp":1760111570000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,10]]},"references-count":40,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25189777"],"URL":"https:\/\/doi.org\/10.3390\/ijms25189777","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,10]]}}}