{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:26:43Z","timestamp":1783729603875,"version":"3.55.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T00:00:00Z","timestamp":1624579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Biomarkers are needed for patient stratification between benign thyroid nodules (BTN) and thyroid cancer (TC) and identifying metastasis in TC. Though plasma <jats:italic>N<\/jats:italic>-glycome profiling has shown potential in the discovery of biomarkers and can provide new insight into the mechanisms involved, little is known about it in TC and BTN. Besides, several studies have indicated associations between abnormal glycosylation and TC. Here, we aimed to explore plasma protein <jats:italic>N<\/jats:italic>-glycome of a TC cohort with regard to their applicability to serve as biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plasma protein <jats:italic>N<\/jats:italic>-glycomes of TC, BTN, and matched healthy controls (HC) were obtained using a robust quantitative strategy based on MALDI-TOF MS and included linkage-specific sialylation information.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Plasma <jats:italic>N<\/jats:italic>-glycans were found to differ between BTN, TC, and HC in main glycosylation features, namely complexity, galactosylation, fucosylation, and sialylation. Four altered glycan traits, which were consecutively decreased in BTN and TC, and classification models based on them showed high potential as biomarkers for discrimination between BTN and TC (\u201cmoderately accurate\u201d to \u201caccurate\u201d). Additionally, strong associations were found between plasma <jats:italic>N<\/jats:italic>-glycans and lymph node metastasis in TC, which added the accuracy of predicting metastasis before surgery to the existing method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We comprehensively evaluated the plasma <jats:italic>N<\/jats:italic>-glycomic changes in patients with TC or BTN for the first time. We determined several <jats:italic>N<\/jats:italic>-glycan biomarkers, some of them have potential in the differential diagnosis of TC, and the others can help to stratify TC patients to low or high risk of lymph node metastasis. The findings enhanced the understanding of TC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.692910","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T07:25:50Z","timestamp":1624605950000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Distinguishing Benign and Malignant Thyroid Nodules and Identifying Lymph Node Metastasis in Papillary Thyroid Cancer by Plasma N-Glycomics"],"prefix":"10.3389","volume":"12","author":[{"given":"Zejian","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karli R.","family":"Reiding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zepeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiequn","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.suc.2014.02.004","article-title":"Evaluation of Thyroid Incidentaloma","volume":"94","author":"Wilhelm","year":"2014","journal-title":"Surg Clin North Am"},{"key":"B2","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1111\/j.1365-2362.2009.02162.x","article-title":"Very High Prevalence of Thyroid Nodules Detected by High Frequency (13 MHz) Ultrasound Examination","volume":"39","author":"Guth","year":"2009","journal-title":"Eur J Clin Invest"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30172-6","article-title":"Thyroid Cancer","volume":"388","author":"Cabanillas","year":"2016","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American Thyroid Association Management Guidelines for Adult Patients With Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.0898","article-title":"The Diagnosis and Management of Thyroid Nodules: A Review","volume":"319","author":"Durante","year":"2018","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1016\/j.surg.2013.07.006","article-title":"Increases in Thyroid Nodule Fine-Needle Aspirations, Operations, and Diagnoses of Thyroid Cancer in the United States","volume":"154","author":"Sosa","year":"2013","journal-title":"Surgery"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1089\/gtmb.2019.0028","article-title":"A Comparative Study of ARHI Imprinted Gene Detection and Fine-Needle Aspiration Cytology in the Differential Diagnosis of Benign and Malignant Thyroid Nodules","volume":"23","author":"Zou","year":"2019","journal-title":"Genet Test Mol Biomarkers"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1159\/000339959","article-title":"The Bethesda System for Reporting Thyroid Cytopathology: A Meta-Analysis","volume":"56","author":"Bongiovanni","year":"2012","journal-title":"Acta Cytol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2012.0043","article-title":"The Prognostic Significance of Nodal Metastases From Papillary Thyroid Carcinoma can be Stratified Based on the Size and Number of Metastatic Lymph Nodes, as Well as the Presence of Extranodal Extension","volume":"22","author":"Randolph","year":"2012","journal-title":"Thyroid"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-016-5691-4","article-title":"The Effect of Prophylactic Central Neck Dissection on Locoregional Recurrence in Papillary Thyroid Cancer After Total Thyroidectomy: A Systematic Review and Meta-Analysis : pCND for the Locoregional Recurrence of Papillary Thyroid Cancer","volume":"24","author":"Zhao","year":"2017","journal-title":"Ann Surg Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.11.008","article-title":"Glycomics Hits the Big Time","volume":"143","author":"Hart","year":"2010","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3383","article-title":"Vertebrate Protein Glycosylation: Diversity, Synthesis and Function","volume":"13","author":"Moremen","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1093\/glycob\/cww086","article-title":"Biological Roles of Glycans","volume":"27","author":"Varki","year":"2017","journal-title":"Glycobiology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/601583","article-title":"Glycosylation Changes on Serum Glycoproteins in Ovarian Cancer may Contribute to Disease Pathogenesis","volume":"25","author":"Saldova","year":"2008","journal-title":"Dis Markers"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25753","article-title":"Serum N-glycome Alterations in Colorectal Cancer Associate With Survival","volume":"9","author":"de Vroome","year":"2018","journal-title":"Oncotarget"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwp134","article-title":"Stability of N-glycan Profiles in Human Plasma","volume":"19","author":"Gornik","year":"2009","journal-title":"Glycobiology"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2016.03.035","article-title":"Towards Personalized Diagnostics Via Longitudinal Study of the Human Plasma N-Glycome","volume":"1860","author":"Hennig","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.3390\/ijms18112262","article-title":"Gastric Cancer Cell Glycosylation as a Modulator of the ErbB2 Oncogenic Receptor","volume":"18","author":"Duarte","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2015.10.016","article-title":"Mechanisms of Disease: The Human N-Glycome","volume":"1860","author":"Lauc","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02120","article-title":"Altered Cell Adhesion and Glycosylation Promote Cancer Immune Suppression and Metastasis","volume":"10","author":"Laubli","year":"2019","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2018.08.005","article-title":"Plasma Protein N-Glycan Signatures of Type 2 Diabetes","volume":"1862","author":"Dotz","year":"2018","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"B22","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.carres.2015.04.019","article-title":"Mass Spectrometry-Based N-linked Glycomic Profiling as a Means for Tracking Pancreatic Cancer Metastasis","volume":"413","author":"Park","year":"2015","journal-title":"Carbohydr Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26262","article-title":"Identification of Novel Serum Biomarkers of Hepatocellular Carcinoma Using Glycomic Analysis","volume":"57","author":"Kamiyama","year":"2013","journal-title":"Hepatology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2019.03.001","article-title":"Serum Protein N-Glycosylation Changes in Multiple Myeloma","volume":"1863","author":"Zhang","year":"2019","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/816595","article-title":"Involvement of Aberrant Glycosylation in Thyroid Cancer","volume":"2010","author":"Miyoshi","year":"2010","journal-title":"J Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2019.113389","article-title":"N-Glycan Profiling of Papillary Thyroid Carcinoma Tissues by MALDI-TOF-MS","volume":"584","author":"Kocak","year":"2019","journal-title":"Anal Biochem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2012.02.001","article-title":"Human IgG Fc-Glycosylation Profiling Reveals Associations With Age, Sex, Female Sex Hormones and Thyroid Cancer","volume":"75","author":"Chen","year":"2012","journal-title":"J Proteomics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1021\/ac500335t","article-title":"High-Throughput Profiling of Protein N-Glycosylation by MALDI-TOF-MS Employing Linkage-Specific Sialic Acid Esterification","volume":"86","author":"Reiding","year":"2014","journal-title":"Anal Chem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.5b00658","article-title":"Massytools: A High-Throughput Targeted Data Processing Tool for Relative Quantitation and Quality Control Developed for Glycomic and Glycoproteomic Maldi-Ms","volume":"14","author":"Jansen","year":"2015","journal-title":"J Proteome Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1021\/ac1027116","article-title":"Cotton HILIC SPE Microtips for Microscale Purification and Enrichment of Glycans and Glycopeptides","volume":"83","author":"Selman","year":"2011","journal-title":"Anal Chem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1021\/pr7008252","article-title":"GlycoWorkbench: A Tool for the Computer-Assisted Annotation of Mass Spectra of Glycans","volume":"7","author":"Ceroni","year":"2008","journal-title":"J Proteome Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s10719-015-9626-2","article-title":"Human Plasma Protein N-Glycosylation","volume":"33","author":"Clerc","year":"2016","journal-title":"Glycoconj J"},{"key":"B33","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/S0065-2423(08)00402-2","article-title":"Human Total Serum N-Glycome","volume":"46","author":"Klein","year":"2008","journal-title":"Adv Clin Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1021\/pr100528k","article-title":"The N-glycome of Human Plasma","volume":"9","author":"Stumpo","year":"2010","journal-title":"J Proteome Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.5b00538","article-title":"Automation of High-Throughput Mass Spectrometry-Based Plasma N-Glycome Analysis With Linkage-Specific Sialic Acid Esterification","volume":"14","author":"Bladergroen","year":"2015","journal-title":"J Proteome Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.9b00557","article-title":"Glyco-CPLL: An Integrated Method for In-Depth and Comprehensive N-Glycoproteome Profiling of Human Plasma","volume":"19","author":"Zhang","year":"2020","journal-title":"J Proteome Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.9b00672","article-title":"Comparative Glycoproteomic Profiling of Human Body Fluid Between Healthy Controls and Patients With Papillary Thyroid Carcinoma","volume":"19","author":"Zhang","year":"2020","journal-title":"J Proteome Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-012-0482-9","article-title":"Translational Biomarker Discovery in Clinical Metabolomics: An Introductory Tutorial","volume":"9","author":"Xia","year":"2013","journal-title":"Metabolomics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.3390\/cancers12061413","article-title":"Prognostic Implications of CD10 and CD15 Expression in Papillary Thyroid Carcinoma","volume":"12","author":"Oh","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2018.8738","article-title":"Knockdown of FUT3 Disrupts the Proliferation, Migration, Tumorigenesis and TGF-beta Induced EMT in Pancreatic Cancer Cells","volume":"16","author":"Zhan","year":"2018","journal-title":"Oncol Lett"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e2968","DOI":"10.1038\/cddis.2017.352","article-title":"miR-125a-3p\/FUT5-FUT6 Axis Mediates Colorectal Cancer Cell Proliferation, Migration, Invasion and Pathological Angiogenesis Via PI3K-Akt Pathway","volume":"8","author":"Liang","year":"2017","journal-title":"Cell Death Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.3439","article-title":"Serum N-Glycome Analysis Reveals Pancreatic Cancer Disease Signatures","volume":"9","author":"Vreeker","year":"2020","journal-title":"Cancer Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1749-6632.2012.06517.x","article-title":"Multifarious Roles of Sialic Acids in Immunity","volume":"1253","author":"Varki","year":"2012","journal-title":"Ann N Y Acad Sci"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/292730","article-title":"In Vivo Clearance of Alpha-1 Acid Glycoprotein Is Influenced by the Extent of Its N-Linked Glycosylation and by Its Interaction With the Vessel Wall","volume":"2012","author":"McCurdy","year":"2012","journal-title":"J BioMed Biotechnol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/1724600818787752","article-title":"Decreased Apolipoprotein A4 and Increased Complement Component 3 as Potential Markers for Papillary Thyroid Carcinoma: A Proteomic Study","volume":"33","author":"Farrokhi Yekta","year":"2018","journal-title":"Int J Biol Markers"},{"key":"B47","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/1476-4598-8-79","article-title":"Discovery and Identification of Potential Biomarkers of Papillary Thyroid Carcinoma","volume":"8","author":"Fan","year":"2009","journal-title":"Mol Cancer"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.2450","article-title":"Tissue and Serum Samples of Patients With Papillary Thyroid Cancer With and Without Benign Background Demonstrate Different Altered Expression of Proteins","volume":"4","author":"Abdullah","year":"2016","journal-title":"PeerJ"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2020.140510","article-title":"Proteomics in Thyroid Cancer and Other Thyroid-Related Diseases: A Review of the Literature","volume":"1868","author":"Ucal","year":"2020","journal-title":"Biochim Biophys Acta Proteins Proteom"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1021\/pr900278c","article-title":"Cell Surface and Secreted Protein\u00a0Profiles of Human Thyroid Cancer Cell Lines Reveal Distinct Glycoprotein Patterns","volume":"8","author":"Arcinas","year":"2009","journal-title":"J Proteome Res"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.05.030","article-title":"Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases","volume":"155","author":"Clerc","year":"2018","journal-title":"Gastroenterology"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.89703","article-title":"Estrogens Regulate Glycosylation of IgG in Women and Men","volume":"2","author":"Ercan","year":"2017","journal-title":"JCI Insight"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2020.152859","article-title":"Breast Cancer Cutaneous Metastases Are Associated to uMUC1 and Sialyl Lewis X and to Highly Malignant Primary Tumors","volume":"216","author":"Luna","year":"2020","journal-title":"Pathol Res Pract"},{"key":"B54","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1177\/1066896908320832","article-title":"E-Selectin and Sialyl Lewis X Expression Is Associated With Lymph Node Metastasis of Invasive Micropapillary Carcinoma of the Breast","volume":"18","author":"Wei","year":"2010","journal-title":"Int J Surg Pathol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s11596-017-1757-1","article-title":"Inhibition of Adhesion and Metastasis of HepG2 Hepatocellular Carcinoma Cells In Vitro by DNA Aptamer Against Sialyl Lewis X","volume":"37","author":"Wang","year":"2017","journal-title":"J Huazhong Univ Sci Technol Med Sci"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.00216.x","article-title":"Positive Correlation Between Sialyl Lewis X Expression and Pathologic Findings in Renal Cell Carcinoma","volume":"67","author":"Tozawa","year":"2005","journal-title":"Kidney Int"},{"key":"B57","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.ando.2019.01.003","article-title":"Proteomic Analysis of the Papillary Thyroid Microcarcinoma","volume":"80","author":"Jin","year":"2019","journal-title":"Ann Endocrinol (Paris)"},{"key":"B58","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s13238-020-00741-7","article-title":"Role of Glycosylation in TGF-Beta Signaling and Epithelial-to-Mesenchymal Transition in Cancer","volume":"12","author":"Zhang","year":"2021","journal-title":"Protein Cell"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.692910\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T07:25:53Z","timestamp":1624605953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.692910\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,25]]},"references-count":58,"alternative-id":["10.3389\/fendo.2021.692910"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.692910","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,25]]},"article-number":"692910"}}