{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T06:47:51Z","timestamp":1776494871631,"version":"3.51.2"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MECONC\/ 29043\/2017"],"award-info":[{"award-number":["PTDC\/MECONC\/ 29043\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/132751\/2017"],"award-info":[{"award-number":["SFRH\/BD\/132751\/2017"]}],"id":[{"id":"10.13039\/501100001871","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:p>Testicular germ cell tumors (TGCTs) are among the most common solid malignancies in young-adult men, and currently most mortality is due to metastatic disease and emergence of resistance to cisplatin. There is some evidence that increased methylation is one mechanism behind this resistance, stemming from individual studies, but approaches based on matched primary and metastatic patient samples are lacking. Herein, we provide an EPIC array-based study of matched primary and metastatic TGCT samples. Histology was the major determinant of overall methylation pattern, but some clustering of samples related to response to cisplatin was observed. Further differential analysis of patients with the same histological subtype (embryonal carcinoma) disclosed a remarkable increase in net methylation levels (at both promoter and CpG site level) in the patient with cisplatin-resistant disease and poor outcome compared to the patient with complete response to chemotherapy. This further confirms the recent results of another study performed on isogenic clones of sensitive and resistant TGCT cell lines. Differentially methylated promoters among groups of samples were mostly not shared, disclosing heterogeneity in patient tissue samples. Finally, gene ontology analysis of cisplatin-resistant samples indicated enrichment of differentially hypermethylated promoters on pathways related to regulation of immune microenvironment, and enrichment of differentially hypomethylated promoters on pathways related to DNA\/chromatin binding and regulation. This data supports not only the use of hypomethylating agents for targeting cisplatin-resistant disease, but also their use in combination with immunotherapies and chromatin remodelers.<\/jats:p>","DOI":"10.1186\/s13148-021-01048-y","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T12:02:26Z","timestamp":1617710546000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Lobo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3151-0367","authenticated-orcid":false,"given":"Vera","family":"Const\u00e2ncio","sequence":"additional","affiliation":[]},{"given":"Pedro","family":"Leite-Silva","sequence":"additional","affiliation":[]},{"given":"Rita","family":"Guimar\u00e3es","sequence":"additional","affiliation":[]},{"given":"Mariana","family":"Cantante","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9265-4324","authenticated-orcid":false,"given":"Isaac","family":"Braga","sequence":"additional","affiliation":[]},{"given":"Joaquina","family":"Maur\u00edcio","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8146-1911","authenticated-orcid":false,"given":"Leendert H. J.","family":"Looijenga","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"issue":"2","key":"1048_CR1","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3390\/ijms20020258","volume":"20","author":"J Lobo","year":"2019","unstructured":"Lobo J, Gillis AJM, Jeronimo C, Henrique R, Looijenga LHJ. Human germ cell tumors are developmental cancers: impact of epigenetics on pathobiology and clinic. Int J Mol Sci. 2019;20(2):65.","journal-title":"Int J Mol Sci"},{"issue":"9","key":"1048_CR2","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/s41568-019-0178-9","volume":"19","author":"JW Oosterhuis","year":"2019","unstructured":"Oosterhuis JW, Looijenga LHJ. Human germ cell tumours from a developmental perspective. Nat Rev Cancer. 2019;19(9):522\u201337.","journal-title":"Nat Rev Cancer"},{"issue":"8","key":"1048_CR3","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1093\/annonc\/mdy217","volume":"29","author":"F Honecker","year":"2018","unstructured":"Honecker F, Aparicio J, Berney D, Beyer J, Bokemeyer C, Cathomas R, et al. ESMO consensus conference on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018;29(8):1658\u201386.","journal-title":"Ann Oncol"},{"key":"1048_CR4","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/978-3-319-43624-1_7","volume":"945","author":"R Lakshminarasimhan","year":"2016","unstructured":"Lakshminarasimhan R, Liang G. The role of DNA methylation in cancer. Adv Exp Med Biol. 2016;945:151\u201372.","journal-title":"Adv Exp Med Biol"},{"issue":"3","key":"1048_CR5","doi-asserted-by":"publisher","first-page":"558","DOI":"10.3390\/cells9030624","volume":"9","author":"V Constancio","year":"2020","unstructured":"Constancio V, Nunes SP, Henrique R, Jeronimo C. DNA methylation-based testing in liquid biopsies as detection and prognostic biomarkers for the four major cancer types. Cells. 2020;9(3):558.","journal-title":"Cells"},{"issue":"4","key":"1048_CR6","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1586\/erm.10.17","volume":"10","author":"VV Levenson","year":"2010","unstructured":"Levenson VV. DNA methylation as a universal biomarker. Expert Rev Mol Diagn. 2010;10(4):481\u20138.","journal-title":"Expert Rev Mol Diagn"},{"issue":"4","key":"1048_CR7","doi-asserted-by":"publisher","first-page":"e0122146","DOI":"10.1371\/journal.pone.0122146","volume":"10","author":"MA Rijlaarsdam","year":"2015","unstructured":"Rijlaarsdam MA, Tax DM, Gillis AJ, Dorssers LC, Koestler DC, de Ridder J, et al. Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. PLoS ONE. 2015;10(4):e0122146.","journal-title":"PLoS ONE"},{"key":"1048_CR8","doi-asserted-by":"publisher","first-page":"15009","DOI":"10.1038\/npjgenmed.2015.9","volume":"1","author":"DAM Noor","year":"2016","unstructured":"Noor DAM, Jeyapalan JN, Alhazmi S, Carr M, Squibb B, Wallace C, et al. Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines. NPJ Genom Med. 2016;1:15009.","journal-title":"NPJ Genom Med"},{"issue":"6","key":"1048_CR9","doi-asserted-by":"publisher","first-page":"e98330","DOI":"10.1371\/journal.pone.0098330","volume":"9","author":"YG van der Zwan","year":"2014","unstructured":"van der Zwan YG, Rijlaarsdam MA, Rossello FJ, Notini AJ, de Boer S, Watkins DN, et al. Seminoma and embryonal carcinoma footprints identified by analysis of integrated genome-wide epigenetic and expression profiles of germ cell cancer cell lines. PLoS ONE. 2014;9(6):e98330.","journal-title":"PLoS ONE"},{"issue":"11","key":"1048_CR10","doi-asserted-by":"publisher","first-page":"3392","DOI":"10.1016\/j.celrep.2018.05.039","volume":"23","author":"H Shen","year":"2018","unstructured":"Shen H, Shih J, Hollern DP, Wang L, Bowlby R, Tickoo SK, et al. Integrated molecular characterization of testicular germ cell tumors. Cell Rep. 2018;23(11):3392\u2013406.","journal-title":"Cell Rep"},{"issue":"11","key":"1048_CR11","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1101\/gr.201293.115","volume":"26","author":"JK Killian","year":"2016","unstructured":"Killian JK, Dorssers LC, Trabert B, Gillis AJ, Cook MB, Wang Y, et al. Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors. Genome Res. 2016;26(11):1490\u2013504.","journal-title":"Genome Res"},{"issue":"2","key":"1048_CR12","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/bjc.2015.408","volume":"114","author":"HH Cheung","year":"2016","unstructured":"Cheung HH, Yang Y, Lee TL, Rennert O, Chan WY. Hypermethylation of genes in testicular embryonal carcinomas. Br J Cancer. 2016;114(2):230\u20136.","journal-title":"Br J Cancer"},{"issue":"4","key":"1048_CR13","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/s41416-019-0381-1","volume":"120","author":"LCJ Dorssers","year":"2019","unstructured":"Dorssers LCJ, Gillis AJM, Stoop H, van Marion R, Nieboer MM, van Riet J, et al. Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development. Br J Cancer. 2019;120(4):444\u201352.","journal-title":"Br J Cancer"},{"key":"1048_CR14","first-page":"1","volume":"66","author":"Z Fazal","year":"2020","unstructured":"Fazal Z, Singh R, Fang F, Bikorimana E, Baldwin H, Corbet A, et al. Hypermethylation and global remodelling of DNA methylation is associated with acquired cisplatin resistance in testicular germ cell tumours. Epigenetics. 2020;66:1\u201314.","journal-title":"Epigenetics"},{"issue":"6","key":"1048_CR15","doi-asserted-by":"publisher","first-page":"148","DOI":"10.3390\/cancers11060796","volume":"11","author":"R Singh","year":"2019","unstructured":"Singh R, Fazal Z, Corbet AK, Bikorimana E, Rodriguez JC, Khan EM, et al. Epigenetic remodeling through downregulation of polycomb repressive complex 2 mediates chemotherapy resistance in testicular germ cell tumors. Cancers. 2019;11(6):148.","journal-title":"Cancers"},{"issue":"1","key":"1048_CR16","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/andr.299","volume":"3","author":"C Jacobsen","year":"2015","unstructured":"Jacobsen C, Honecker F. Cisplatin resistance in germ cell tumours: models and mechanisms. Andrology. 2015;3(1):111\u201321.","journal-title":"Andrology"},{"issue":"4","key":"1048_CR17","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1002\/path.2725","volume":"221","author":"H Wermann","year":"2010","unstructured":"Wermann H, Stoop H, Gillis AJ, Honecker F, van Gurp RJ, Ammerpohl O, et al. Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J Pathol. 2010;221(4):433\u201342.","journal-title":"J Pathol"},{"issue":"9","key":"1048_CR18","doi-asserted-by":"publisher","first-page":"253","DOI":"10.3390\/cancers11091316","volume":"11","author":"V Bakardjieva-Mihaylova","year":"2019","unstructured":"Bakardjieva-Mihaylova V, Skvarova Kramarzova K, Slamova M, Svaton M, Rejlova K, Zaliova M, et al. Molecular basis of cisplatin resistance in testicular germ cell tumors. Cancers. 2019;11(9):253.","journal-title":"Cancers"},{"key":"1048_CR19","first-page":"25","volume":"4","author":"ML Cheng","year":"2020","unstructured":"Cheng ML, Donoghue MTA, Audenet F, Wong NC, Pietzak EJ, Bielski CM, et al. Germ cell tumor molecular heterogeneity revealed through analysis of primary and metastasis pairs. JCO Precis Oncol. 2020;4:25.","journal-title":"JCO Precis Oncol"},{"issue":"3","key":"1048_CR20","doi-asserted-by":"publisher","first-page":"e0213815","DOI":"10.1371\/journal.pone.0213815","volume":"14","author":"MT Barrett","year":"2019","unstructured":"Barrett MT, Lenkiewicz E, Malasi S, Stanton M, Slack J, Andrews P, et al. Clonal analyses of refractory testicular germ cell tumors. PLoS ONE. 2019;14(3):e0213815.","journal-title":"PLoS ONE"},{"issue":"1","key":"1048_CR21","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.euf.2018.07.013","volume":"6","author":"A Necchi","year":"2020","unstructured":"Necchi A, Bratslavsky G, Corona RJ, Chung JH, Millis SZ, Elvin JA, et al. Genomic characterization of testicular germ cell tumors relapsing after chemotherapy. Eur Urol Focus. 2020;6(1):122\u201330.","journal-title":"Eur Urol Focus"},{"issue":"1","key":"1048_CR22","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1038\/s41467-020-15768-x","volume":"11","author":"C Loveday","year":"2020","unstructured":"Loveday C, Litchfield K, Proszek PZ, Cornish AJ, Santo F, Levy M, et al. Genomic landscape of platinum resistant and sensitive testicular cancers. Nat Commun. 2020;11(1):2189.","journal-title":"Nat Commun"},{"issue":"51","key":"1048_CR23","doi-asserted-by":"publisher","first-page":"56","DOI":"10.18632\/oncotarget.27844","volume":"11","author":"J Ro\u0161ka","year":"2020","unstructured":"Ro\u0161ka J, Wachsmannov\u00e1 L, Hurbanov\u00e1 L, \u0160est\u00e1kov\u00e1 Z, Mueller T, Jurkovi\u010dov\u00e1 D, et al. Differential gene expression in cisplatin-resistant and -sensitive testicular germ cell tumor cell lines. Oncotarget. 2020;11(51):56.","journal-title":"Oncotarget"},{"key":"1048_CR24","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.humpath.2018.07.016","volume":"82","author":"J Lobo","year":"2018","unstructured":"Lobo J, Costa AL, Vilela-Salgueiro B, Rodrigues A, Guimaraes R, Cantante M, et al. Testicular germ cell tumors: revisiting a series in light of the new WHO classification and AJCC staging systems, focusing on challenges for pathologists. Hum Pathol. 2018;82:113\u201324.","journal-title":"Hum Pathol"},{"issue":"1","key":"1048_CR25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s13059-019-1664-9","volume":"20","author":"F Muller","year":"2019","unstructured":"Muller F, Scherer M, Assenov Y, Lutsik P, Walter J, Lengauer T, et al. RnBeads 2.0: comprehensive analysis of DNA methylation data. Genome Biol. 2019;20(1):55.","journal-title":"Genome Biol"},{"key":"1048_CR26","doi-asserted-by":"publisher","first-page":"102054","DOI":"10.1016\/j.ctrv.2020.102054","volume":"88","author":"G de Vries","year":"2020","unstructured":"de Vries G, Rosas-Plaza X, van Vugt M, Gietema JA, de Jong S. Testicular cancer: determinants of cisplatin sensitivity and novel therapeutic opportunities. Cancer Treat Rev. 2020;88:102054.","journal-title":"Cancer Treat Rev"},{"issue":"11","key":"1048_CR27","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1007\/s11912-018-0730-x","volume":"20","author":"S Schmidtova","year":"2018","unstructured":"Schmidtova S, Kalavska K, Kucerova L. Molecular mechanisms of cisplatin chemoresistance and its circumventing in testicular germ cell tumors. Curr Oncol Rep. 2018;20(11):88.","journal-title":"Curr Oncol Rep"},{"key":"1048_CR28","doi-asserted-by":"publisher","first-page":"e12","DOI":"10.1017\/erm.2013.13","volume":"15","author":"R Koster","year":"2013","unstructured":"Koster R, van Vugt MA, Timmer-Bosscha H, Gietema JA, de Jong S. Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer. Expert Rev Mol Med. 2013;15:e12.","journal-title":"Expert Rev Mol Med"},{"issue":"6","key":"1048_CR29","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1093\/annonc\/mdg242","volume":"14","author":"F Mayer","year":"2003","unstructured":"Mayer F, Honecker F, Looijenga LH, Bokemeyer C. Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors. Ann Oncol. 2003;14(6):825\u201332.","journal-title":"Ann Oncol"},{"issue":"3","key":"1048_CR30","first-page":"580","volume":"2","author":"R Singh","year":"2019","unstructured":"Singh R, Fazal Z, Freemantle SJ, Spinella MJ. Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors. Cancer Drug Resist. 2019;2(3):580\u201394.","journal-title":"Cancer Drug Resist"},{"key":"1048_CR31","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1476-4598-3-16","volume":"3","author":"S Koul","year":"2004","unstructured":"Koul S, McKiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, et al. Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. Mol Cancer. 2004;3:16.","journal-title":"Mol Cancer"},{"issue":"31","key":"1048_CR32","doi-asserted-by":"publisher","first-page":"50608","DOI":"10.18632\/oncotarget.11167","volume":"8","author":"C Martinelli","year":"2017","unstructured":"Martinelli C, Lengert AVH, Carcano FM, Silva ECA, Brait M, Lopes LF, et al. MGMT and CALCA promoter methylation are associated with poor prognosis in testicular germ cell tumor patients. Oncotarget. 2017;8(31):50608\u201317.","journal-title":"Oncotarget"},{"issue":"1","key":"1048_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4149\/neo_2019_190318N244","volume":"67","author":"J Roska","year":"2020","unstructured":"Roska J, Jurkovicova D. Understanding the crosstalk of molecular factors and signaling pathways reveals novel biomarkers of cisplatin resistance in testicular germ cell tumors. Neoplasma. 2020;67(1):1\u201314.","journal-title":"Neoplasma"},{"issue":"24","key":"1048_CR34","doi-asserted-by":"publisher","first-page":"9360","DOI":"10.1158\/0008-5472.CAN-09-1490","volume":"69","author":"MJ Beyrouthy","year":"2009","unstructured":"Beyrouthy MJ, Garner KM, Hever MP, Freemantle SJ, Eastman A, Dmitrovsky E, et al. High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors. Cancer Res. 2009;69(24):9360\u20136.","journal-title":"Cancer Res"},{"issue":"12","key":"1048_CR35","doi-asserted-by":"publisher","first-page":"e53003","DOI":"10.1371\/journal.pone.0053003","volume":"7","author":"BK Biswal","year":"2012","unstructured":"Biswal BK, Beyrouthy MJ, Hever-Jardine MP, Armstrong D, Tomlinson CR, Christensen BC, et al. Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS ONE. 2012;7(12):e53003.","journal-title":"PLoS ONE"},{"issue":"2","key":"1048_CR36","doi-asserted-by":"publisher","first-page":"2949","DOI":"10.18632\/oncotarget.13811","volume":"8","author":"C Albany","year":"2017","unstructured":"Albany C, Hever-Jardine MP, von Herrmann KM, Yim CY, Tam J, Warzecha JM, et al. Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. Oncotarget. 2017;8(2):2949\u201359.","journal-title":"Oncotarget"},{"issue":"1","key":"1048_CR37","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3390\/ijms20010021","volume":"20","author":"C Oing","year":"2018","unstructured":"Oing C, Verem I, Mansour WY, Bokemeyer C, Dyshlovoy S, Honecker F. 5-Azacitidine exerts prolonged pro-apoptotic effects and overcomes cisplatin-resistance in non-seminomatous germ cell tumor cells. Int J Mol Sci. 2018;20(1):56.","journal-title":"Int J Mol Sci"},{"key":"1048_CR38","first-page":"66","volume":"5","author":"C Albany","year":"2020","unstructured":"Albany C, Fazal Z, Singh R, Bikorimana E, Adra N, Hanna NH, et al. A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer. Cancer Med. 2020;5:66.","journal-title":"Cancer Med."},{"issue":"1","key":"1048_CR39","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1093\/annonc\/mdx680","volume":"29","author":"N Adra","year":"2018","unstructured":"Adra N, Einhorn LH, Althouse SK, Ammakkanavar NR, Musapatika D, Albany C, et al. Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206. Ann Oncol. 2018;29(1):209\u201314.","journal-title":"Ann Oncol"},{"issue":"1","key":"1048_CR40","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.eururo.2018.09.010","volume":"75","author":"A Necchi","year":"2019","unstructured":"Necchi A, Giannatempo P, Raggi D, Mariani L, Colecchia M, Fare E, et al. An open-label randomized phase 2 study of durvalumab alone or in combination with tremelimumab in patients with advanced germ cell tumors (APACHE): results from the first planned interim analysis. Eur Urol. 2019;75(1):201\u20133.","journal-title":"Eur Urol"},{"issue":"4","key":"1048_CR41","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1007\/s10637-019-00805-4","volume":"37","author":"M Mego","year":"2019","unstructured":"Mego M, Svetlovska D, Chovanec M, Reckova M, Rejlekova K, Obertova J, et al. Phase II study of avelumab in multiple relapsed\/refractory germ cell cancer. Invest New Drugs. 2019;37(4):748\u201354.","journal-title":"Invest New Drugs"},{"issue":"10","key":"1048_CR42","doi-asserted-by":"publisher","first-page":"8568","DOI":"10.3390\/cancers11101535","volume":"11","author":"J Lobo","year":"2019","unstructured":"Lobo J, Rodrigues A, Guimaraes R, Cantante M, Lopes P, Mauricio J, et al. Detailed characterization of immune cell infiltrate and expression of immune checkpoint molecules PD-L1\/CTLA-4 and MMR proteins in testicular germ cell tumors disclose novel disease biomarkers. Cancers. 2019;11(10):8568.","journal-title":"Cancers"},{"issue":"3","key":"1048_CR43","doi-asserted-by":"publisher","first-page":"568","DOI":"10.3390\/ijms21030829","volume":"21","author":"J Lobo","year":"2020","unstructured":"Lobo J, Jeronimo C, Henrique R. Targeting the immune system and epigenetic landscape of urological tumors. Int J Mol Sci. 2020;21(3):568.","journal-title":"Int J Mol Sci"},{"issue":"4","key":"1048_CR44","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41585-019-0154-x","volume":"16","author":"S Jostes","year":"2019","unstructured":"Jostes S, Nettersheim D, Schorle H. Epigenetic drugs and their molecular targets in testicular germ cell tumours. Nat Rev Urol. 2019;16(4):245\u201359.","journal-title":"Nat Rev Urol"},{"key":"1048_CR45","first-page":"1","volume":"56","author":"AR Cardoso","year":"2020","unstructured":"Cardoso AR, Lobo J, Miranda-Goncalves V, Henrique R, Jeronimo C. Epigenetic alterations as therapeutic targets in Testicular Germ Cell Tumours: current and future application of \u201cepidrugs.\u201d Epigenetic 2020;56:1\u201320","journal-title":"Epigenetics"}],"container-title":["Clinical Epigenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-021-01048-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13148-021-01048-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-021-01048-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T03:05:20Z","timestamp":1675134320000},"score":1,"resource":{"primary":{"URL":"https:\/\/clinicalepigeneticsjournal.biomedcentral.com\/articles\/10.1186\/s13148-021-01048-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1048"],"URL":"https:\/\/doi.org\/10.1186\/s13148-021-01048-y","relation":{},"ISSN":["1868-7075","1868-7083"],"issn-type":[{"value":"1868-7075","type":"print"},{"value":"1868-7083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,6]]},"assertion":[{"value":"31 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Ethics Committee (CES-IPO-1\/018) of the Portuguese Oncology Institute of Porto, Portugal. All procedures performed in tasks involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"70"}}