{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:11:29Z","timestamp":1790226689636,"version":"4.1.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100024231","name":"Dr. Helmut Legerlotz-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100024231","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005713","name":"Technische Universit\u00e4t M\u00fcnchen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005713","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Epigenet"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most common histologic subtype, squamous cell carcinoma, can stem from various tumor primary sites, including the oral cavity, oropharynx, larynx, head and neck skin, lungs, and esophagus. DNA methylation profiles are highly tissue-specific and have been successfully used to classify tissue origin. We therefore developed a support vector machine (SVM) classifier trained with publicly available DNA methylation profiles of commonly cervically metastasizing squamous cell carcinomas (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20091103) in order to identify the primary tissue of origin of our own cohort of squamous cell hnCUP patient\u2019s samples (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200928). Methylation analysis was performed with Infinium MethylationEPIC v1.0 BeadChip by Illumina.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The SVM algorithm achieved the highest overall accuracy of tested classifiers, with 87%. Squamous cell hnCUP samples on DNA methylation level resembled squamous cell carcinomas commonly metastasizing into cervical lymph nodes. The most frequently predicted cancer localization was the oral cavity in 11 cases (39%), followed by the oropharynx and larynx (both 7, 25%), skin (2, 7%), and esophagus (1, 4%). These frequencies concord with the expected distribution of lymph node metastases in epidemiological studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>On DNA methylation level, hnCUP is comparable to primary tumor tissue cancer types that commonly metastasize to cervical lymph nodes. Our SVM-based classifier can accurately predict these cancers\u2019 tissues of origin and could significantly reduce the invasiveness of hnCUP diagnostics and enable a more precise therapy after clinical validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13148-024-01657-3","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T17:40:16Z","timestamp":1711388416000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Head and neck cancer of unknown primary: unveiling primary tumor sites through machine learning on DNA methylation profiles"],"prefix":"10.1186","volume":"16","author":[{"given":"Leonhard","family":"Stark","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Kasajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"St\u00f6gbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schmidl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Rinecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Holzmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"F\u00e4rber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Pfarr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Steiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Wollenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Ruland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,25]]},"reference":[{"issue":"3","key":"1657_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209\u201349.","journal-title":"CA Cancer J Clin"},{"issue":"2","key":"1657_CR2","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0167-8140(00)00172-9","volume":"55","author":"C Grau","year":"2000","unstructured":"Grau C, Johansen LV, Jakobsen J, Geertsen P, Andersen E, Jensen BB. Cervical lymph node metastases from unknown primary tumours: results from a national survey by the Danish society for head and neck oncology. Radiother Oncol. 2000;55(2):121\u20139.","journal-title":"Radiother Oncol"},{"issue":"12","key":"1657_CR3","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1002\/lary.20638","volume":"119","author":"M Cianchetti","year":"2009","unstructured":"Cianchetti M, Mancuso AA, Amdur RJ, Werning JW, Kirwan J, Morris CG, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348\u201354.","journal-title":"Laryngoscope"},{"issue":"1","key":"1657_CR4","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/hed.21898","volume":"35","author":"P Strojan","year":"2013","unstructured":"Strojan P, Ferlito A, Medina JE, Woolgar JA, Rinaldo A, Robbins KT, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck. 2013;35(1):123\u201332.","journal-title":"Head Neck"},{"issue":"1","key":"1657_CR5","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S0167-8140(98)00082-6","volume":"49","author":"P Strojan","year":"1998","unstructured":"Strojan P, Anicin A. Combined surgery and postoperative radiotherapy for cervical lymph node metastases from an unknown primary tumour. Radiother Oncol. 1998;49(1):33\u201340.","journal-title":"Radiother Oncol"},{"issue":"8","key":"1657_CR6","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1007\/s00259-002-0819-0","volume":"29","author":"G Regelink","year":"2002","unstructured":"Regelink G, Brouwer J, de Bree R, Pruim J, van der Laan BF, Vaalburg W, et al. Detection of unknown primary tumours and distant metastases in patients with cervical metastases: value of FDG-PET versus conventional modalities. Eur J Nucl Med Mol Imaging. 2002;29(8):1024\u201330.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"8","key":"1657_CR7","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1007\/s00405-003-0585-z","volume":"260","author":"WJ Issing","year":"2003","unstructured":"Issing WJ, Taleban B, Tauber S. Diagnosis and management of carcinoma of unknown primary in the head and neck. Eur Arch Otorhinolaryngol. 2003;260(8):436\u201343.","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"2","key":"1657_CR8","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41416-018-0332-2","volume":"120","author":"AM Conway","year":"2019","unstructured":"Conway AM, Mitchell C, Kilgour E, Brady G, Dive C, Cook N. Molecular characterisation and liquid biomarkers in Carcinoma of unknown primary (CUP): taking the \u201cU\u201d out of \u201cCUP.\u201d Br J Cancer. 2019;120(2):141\u201353.","journal-title":"Br J Cancer"},{"issue":"7","key":"1657_CR9","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1055\/s-2000-4641","volume":"79","author":"S Gottschlich","year":"2000","unstructured":"Gottschlich S, Schuhmacher O, G\u00f6r\u00f6gh T, Hoffmann M, Maune S. Analysis of the p53 gene status of lymph node metastasis in the head and neck region in occult primary cancer. Laryngorhinootologie. 2000;79(7):434\u20137.","journal-title":"Laryngorhinootologie"},{"issue":"9824","key":"1657_CR10","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1016\/S0140-6736(11)61178-1","volume":"379","author":"N Pavlidis","year":"2012","unstructured":"Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. The Lancet. 2012;379(9824):1428\u201335.","journal-title":"The Lancet"},{"issue":"1","key":"1657_CR11","doi-asserted-by":"publisher","first-page":"4485","DOI":"10.1038\/s41467-022-31866-4","volume":"13","author":"L M\u00f6hrmann","year":"2022","unstructured":"M\u00f6hrmann L, Werner M, Ole\u015b M, Mock A, Uhrig S, Jahn A, et al. Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity. Nat Commun. 2022;13(1):4485.","journal-title":"Nat Commun"},{"issue":"6","key":"1657_CR12","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/BF03256342","volume":"13","author":"FA Greco","year":"2009","unstructured":"Greco FA, Erlander MG. Molecular classification of cancers of unknown primary site. Mol Diagn Ther. 2009;13(6):367\u201373.","journal-title":"Mol Diagn Ther"},{"issue":"13","key":"1657_CR13","doi-asserted-by":"publisher","first-page":"3919","DOI":"10.7150\/jca.42880","volume":"11","author":"AT Alshareeda","year":"2020","unstructured":"Alshareeda AT, Al-Sowayan BS, Alkharji RR, Aldosari SM, Al Subayyil AM, Alghuwainem A. Cancer of unknown primary site: real entity or misdiagnosed disease? J Cancer. 2020;11(13):3919\u201331.","journal-title":"J Cancer"},{"issue":"4","key":"1657_CR14","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1002\/path.5845","volume":"256","author":"M Leitheiser","year":"2022","unstructured":"Leitheiser M, Capper D, Seegerer P, Lehmann A, Sch\u00fcller U, M\u00fcller KR, et al. Machine learning models predict the primary sites of head and neck squamous cell carcinoma metastases based on DNA methylation. J Pathol. 2022;256(4):378\u201387.","journal-title":"J Pathol"},{"issue":"2","key":"1657_CR15","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s00428-023-03708-1","volume":"484","author":"SW Lorkowski","year":"2024","unstructured":"Lorkowski SW, Dermawan JK, Rubin BP. The practical utility of AI-assisted molecular profiling in the diagnosis and management of cancer of unknown primary: an updated review. Virchows Arch. 2024;484(2):369\u201375.","journal-title":"Virchows Arch"},{"issue":"1","key":"1657_CR16","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41467-020-20603-4","volume":"12","author":"C Koelsche","year":"2021","unstructured":"Koelsche C, Schrimpf D, Stichel D, Sill M, Sahm F, Reuss DE, et al. Sarcoma classification by DNA methylation profiling. Nat Commun. 2021;12(1):498.","journal-title":"Nat Commun"},{"issue":"5","key":"1657_CR17","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/S1470-2045(17)30155-9","volume":"18","author":"F Sahm","year":"2017","unstructured":"Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 2017;18(5):682\u201394.","journal-title":"Lancet Oncol"},{"issue":"1","key":"1657_CR18","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s13148-022-01365-w","volume":"14","author":"S Roohani","year":"2022","unstructured":"Roohani S, Ehret F, Perez E, Capper D, Jarosch A, Fl\u00f6rcken A, et al. Sarcoma classification by DNA methylation profiling in clinical everyday life: the Charit\u00e9 experience. Clin Epigenet. 2022;14(1):149.","journal-title":"Clin Epigenet"},{"issue":"10","key":"1657_CR19","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/S1470-2045(16)30297-2","volume":"17","author":"S Moran","year":"2016","unstructured":"Moran S, Martinez-Cardus A, Sayols S, Musulen E, Balana C, Estival-Gonzalez A, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 2016;17(10):1386\u201395.","journal-title":"Lancet Oncol"},{"issue":"509","key":"1657_CR20","doi-asserted-by":"publisher","first-page":"8513","DOI":"10.1126\/scitranslmed.aaw8513","volume":"11","author":"P Jurmeister","year":"2019","unstructured":"Jurmeister P, Bockmayr M, Seegerer P, Bockmayr T, Treue D, Montavon G, et al. Machine learning analysis of DNA methylation profiles distinguishes primary lung squamous cell carcinomas from head and neck metastases. Sci Transl Med. 2019;11(509):8513.","journal-title":"Sci Transl Med"},{"issue":"S1","key":"1657_CR21","doi-asserted-by":"publisher","first-page":"E2374","DOI":"10.1002\/hed.24344","volume":"38","author":"F L\u00f3pez","year":"2016","unstructured":"L\u00f3pez F, Rodrigo JP, Silver CE, Haigentz M Jr, Bishop JA, Strojan P, et al. Cervical lymph node metastases from remote primary tumor sites. Head Neck. 2016;38(S1):E2374\u201385.","journal-title":"Head Neck"},{"issue":"12","key":"1657_CR22","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1002\/ijc.25516","volume":"127","author":"J Ferlay","year":"2010","unstructured":"Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin D. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 200. Int J Cancer. 2010;127(12):2893\u2013917.","journal-title":"Int J Cancer"},{"issue":"1","key":"1657_CR23","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1046\/j.1442-2050.2003.00286.x","volume":"16","author":"S Nakagawa","year":"2003","unstructured":"Nakagawa S, Nishimaki T, Kosugi S, Ohashi M, Kanda T, Hatakeyama K. Cervical lymphadenectomy is beneficial for patients with carcinoma of the upper and mid-thoracic esophagus. Dis Esophagus. 2003;16(1):4\u20138.","journal-title":"Dis Esophagus"},{"issue":"5","key":"1657_CR24","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1007\/s00405-003-0678-8","volume":"261","author":"S Wenzel","year":"2004","unstructured":"Wenzel S, Sagowski C, Kehrl W, Metternich F. The prognostic impact of metastatic pattern of lymph nodes in patients with oral and oropharyngeal squamous cell carcinomas. Eur Arch Oto-Rhino-Laryngol Head Neck. 2004;261(5):270\u20135.","journal-title":"Eur Arch Oto-Rhino-Laryngol Head Neck"},{"issue":"9","key":"1657_CR25","doi-asserted-by":"publisher","first-page":"3006","DOI":"10.1002\/cam4.2902","volume":"9","author":"X Zhu","year":"2020","unstructured":"Zhu X, Zhao M, Zhou L, Zhang M, Cao P, Tao L. Significance of examined lymph nodes number and metastatic lymph nodes ratio in overall survival and adjuvant treatment decision in resected laryngeal carcinoma. Cancer Med. 2020;9(9):3006\u201314.","journal-title":"Cancer Med"},{"issue":"6","key":"1657_CR26","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.jaad.2012.11.037","volume":"68","author":"PS Karia","year":"2013","unstructured":"Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957\u201366.","journal-title":"J Am Acad Dermatol"},{"key":"1657_CR27","unstructured":"NIH. The cancer genome atlas program\u2014national cancer institute. 2020."},{"issue":"1","key":"1657_CR28","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41467-018-03025-1","volume":"9","author":"M Rodr\u00edguez-Paredes","year":"2018","unstructured":"Rodr\u00edguez-Paredes M, Bormann F, Raddatz G, Gutekunst J, Lucena-Porcel C, K\u00f6hler F, et al. Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin. Nat Commun. 2018;9(1):577.","journal-title":"Nat Commun"},{"issue":"1","key":"1657_CR29","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13569-019-0113-6","volume":"9","author":"C Koelsche","year":"2019","unstructured":"Koelsche C, Stichel D, Griewank KG, Schrimpf D, Reuss DE, Bewerunge-Hudler M, et al. Genome\u2013wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype. Clin Sarcoma Res. 2019;9(1):2.","journal-title":"Clin Sarcoma Res"},{"issue":"10","key":"1657_CR30","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","volume":"30","author":"MJ Aryee","year":"2014","unstructured":"Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, et al. Minfi: a flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30(10):1363\u20139.","journal-title":"Bioinformatics"},{"issue":"4","key":"1657_CR31","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1093\/bioinformatics\/btw691","volume":"33","author":"JP Fortin","year":"2017","unstructured":"Fortin JP, Triche TJ Jr, Hansen KD. Preprocessing, normalization and integration of the illumina humanmethylationEPIC array with minfi. Bioinformatics. 2017;33(4):558\u201360.","journal-title":"Bioinformatics"},{"issue":"1","key":"1657_CR32","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3390\/biomedicines6010006","volume":"6","author":"D Didona","year":"2018","unstructured":"Didona D, Paolino G, Bottoni U, Cantisani C. Non melanoma skin cancer pathogenesis overview. Biomedicines. 2018;6(1):6.","journal-title":"Biomedicines"},{"key":"1657_CR33","doi-asserted-by":"publisher","first-page":"7235","DOI":"10.2147\/CMAR.S319179","volume":"13","author":"M Pinkiewicz","year":"2021","unstructured":"Pinkiewicz M, Dorobisz K, Zato\u0144ski T. A systematic review of cancer of unknown primary in the head and neck region. Cancer Manag Res. 2021;13:7235\u201341.","journal-title":"Cancer Manag Res"},{"issue":"10","key":"1657_CR34","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1007\/s11547-019-01060-6","volume":"124","author":"M Kawaguchi","year":"2019","unstructured":"Kawaguchi M, Kato H, Matsuo M. CT and MRI features of scalp lesions. Radiol Med. 2019;124(10):1049\u201361.","journal-title":"Radiol Med"},{"issue":"Suppl 8","key":"1657_CR35","doi-asserted-by":"publisher","first-page":"S689","DOI":"10.21037\/jtd.2017.06.57","volume":"9","author":"HC Yip","year":"2017","unstructured":"Yip HC, Chiu PW. Endoscopic diagnosis and management of early squamous cell carcinoma of esophagus. J Thorac Dis. 2017;9(Suppl 8):S689\u201396.","journal-title":"J Thorac Dis"},{"issue":"6","key":"1657_CR36","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1111\/ans.13417","volume":"86","author":"L Buckley","year":"2016","unstructured":"Buckley L, Gupta R, Ashford B, Jabbour J, Clark JR. Oropharyngeal cancer and human papilloma virus: evolving diagnostic and management paradigms. ANZ J Surg. 2016;86(6):442\u20137.","journal-title":"ANZ J Surg"},{"issue":"7","key":"1657_CR37","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.prp.2017.01.023","volume":"213","author":"H Wang","year":"2017","unstructured":"Wang H, Deng F, Liu Q, Ma Y. Prognostic significance of lymph node metastasis in esophageal squamous cell carcinoma. Pathol Res Pract. 2017;213(7):842\u20137.","journal-title":"Pathol Res Pract"},{"issue":"5","key":"1657_CR38","doi-asserted-by":"publisher","first-page":"329","DOI":"10.5090\/kjtcs.2017.50.5.329","volume":"50","author":"Y Kang","year":"2017","unstructured":"Kang Y, Hwang Y, Lee HJ, Park IK, Kim YT, Kang CH. Patterns and prognostic significance of cervical lymph node metastasis and the efficacy of cervical node dissection in esophageal cancer. Korean J Thorac Cardiovasc Surg. 2017;50(5):329\u201338.","journal-title":"Korean J Thorac Cardiovasc Surg"},{"issue":"6","key":"1657_CR39","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1002\/1097-0142(197206)29:6<1446::AID-CNCR2820290604>3.0.CO;2-C","volume":"29","author":"R Lindberg","year":"1972","unstructured":"Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer. 1972;29(6):1446\u20139.","journal-title":"Cancer"},{"issue":"6\u20137","key":"1657_CR40","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1080\/15592294.2019.1700003","volume":"15","author":"K Cheung","year":"2020","unstructured":"Cheung K, Burgers MJ, Young DA, Cockell S, Reynard LN. Correlation of infinium humanmethylation450K and MethylationEPIC BeadChip arrays in cartilage. Epigenetics. 2020;15(6\u20137):594\u2013603.","journal-title":"Epigenetics"},{"issue":"12","key":"1657_CR41","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1080\/15592294.2019.1634975","volume":"14","author":"N Fernandez-Jimenez","year":"2019","unstructured":"Fernandez-Jimenez N, Allard C, Bouchard L, Perron P, Bustamante M, Bilbao JR, et al. Comparison of Illumina 450K and EPIC arrays in placental DNA methylation. Epigenetics. 2019;14(12):1177\u201382.","journal-title":"Epigenetics"},{"issue":"8","key":"1657_CR42","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/nmeth.3035","volume":"11","author":"SA Smallwood","year":"2014","unstructured":"Smallwood SA, Lee HJ, Angermueller C, Krueger F, Saadeh H, Peat J, et al. Single-cell genome\u2013wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods. 2014;11(8):817\u201320.","journal-title":"Nat Methods"},{"issue":"4","key":"1657_CR43","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1002\/hed.20734","volume":"30","author":"J Johansen","year":"2008","unstructured":"Johansen J, Buus S, Loft A, Keiding S, Overgaard M, Hansen HS, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck. 2008;30(4):471\u20138.","journal-title":"Head Neck"},{"issue":"2","key":"1657_CR44","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.oraloncology.2014.10.018","volume":"51","author":"G Fotopoulos","year":"2015","unstructured":"Fotopoulos G, Pavlidis N. The role of human papilloma virus and p16 in occult primary of the head and neck: a comprehensive review of the literature. Oral Oncol. 2015;51(2):119\u201323.","journal-title":"Oral Oncol"},{"issue":"5","key":"1657_CR45","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/nrc.2018.11","volume":"18","author":"CR Leemans","year":"2018","unstructured":"Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer. 2018;18(5):269\u201382.","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"1657_CR46","doi-asserted-by":"publisher","first-page":"R5","DOI":"10.1186\/bcr2468","volume":"12","author":"V Popovici","year":"2010","unstructured":"Popovici V, Chen W, Gallas BD, Hatzis C, Shi W, Samuelson FW, et al. Effect of training-sample size and classification difficulty on the accuracy of genomic predictors. Breast Cancer Res. 2010;12(1):R5.","journal-title":"Breast Cancer Res"},{"issue":"2","key":"1657_CR47","doi-asserted-by":"publisher","first-page":"239","DOI":"10.2217\/epi.09.33","volume":"1","author":"M Ehrlich","year":"2009","unstructured":"Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics. 2009;1(2):239\u201359.","journal-title":"Epigenomics"}],"container-title":["Clinical Epigenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-024-01657-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13148-024-01657-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-024-01657-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T17:40:22Z","timestamp":1711388422000},"score":1,"resource":{"primary":{"URL":"https:\/\/clinicalepigeneticsjournal.biomedcentral.com\/articles\/10.1186\/s13148-024-01657-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,25]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1657"],"URL":"https:\/\/doi.org\/10.1186\/s13148-024-01657-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3763132\/v1","asserted-by":"object"}]},"ISSN":["1868-7083"],"issn-type":[{"value":"1868-7083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,25]]},"assertion":[{"value":"16 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study has received approval from the local ethics committee (Technical University of Munich, 285\/20 S-KH).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"A positive vote from the institutional review board was obtained for the retrospective inclusion of probes.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors declare no financial interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"47"}}