{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:11:49Z","timestamp":1788894709995,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T00:00:00Z","timestamp":1662336000000},"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. Oncol."],"abstract":"<jats:p>CNS germ cell tumors (GCTs) preferentially occur in pediatric and adolescent patients. GCTs are located predominantly in the neurohypophysis and the pineal gland. Histopathologically, GCTs are broadly classified into germinomas and non-germinomatous GCTs (NGGCTs). In general, germinoma responds well to chemotherapy and radiation therapy, with a 10-year overall survival (OS) rate of approximately 90%. In contrast, NGGCTs have a less favorable prognosis, with a five-year OS of approximately 70%. Germinomas are typically treated with platinum-based chemotherapy and whole-ventricular radiation therapy, while mature teratomas can be surgically cured. Other NGGCTs require intensive chemotherapy with radiation therapy, including whole brain or craniospinal irradiation, depending on the dissemination status and protocols. Long-term treatment-related sequelae, including secondary neoplasms and cerebrovascular events, have been well recognized. These late effects have a tremendous impact in later life, especially since patients are mostly affected in childhood or young adults. Intending to minimize the treatment burden on patients, the identification of biomarkers for treatment stratification and evaluation of treatment response is of critical importance. Recently, tumor cell content in germinomas has been shown to be closely related to prognosis, suggesting that cases with low tumor cell content may be safely treated with a less intensive regimen. Among the copy number alterations, the 12p gain is the most prominent and has been shown to be a negative prognostic factor in NGGCTs. MicroRNA clusters (mir-371-373) were also revealed to be a hallmark of GCTs, demonstrating the potential for the application of liquid biopsy in the diagnosis and detection of recurrence. Recurrent mutations have been detected in the MAPK or PI3K pathways, most typically in <jats:italic>KIT<\/jats:italic> and <jats:italic>MTOR<\/jats:italic> and low genome-wide methylation has been demonstrated in germinoma; this most likely reflects the cell-of-origin primordial germ cells for this tumor type. These alterations can also be leveraged for liquid biopsies of cell-free DNA and may potentially be targeted for treatment in the future. Advancements in basic research will be translated into clinical practice and can directly impact patient management. Additional understanding of the biology and pathogenesis of GCTs will lead to the development of better-stratified clinical trials, ultimately resulting in improved treatment outcomes and a reduction in long-term treatment-related adverse effects.<\/jats:p>","DOI":"10.3389\/fonc.2022.982608","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T05:44:50Z","timestamp":1662356690000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Biomarkers for risk-based treatment modifications for CNS germ cell tumors: Updates on biological underpinnings, clinical trials, and future directions"],"prefix":"10.3389","volume":"12","author":[{"given":"Hirokazu","family":"Takami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Ichimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noz139","article-title":"Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT consortium","volume":"21","author":"Takami","year":"2019","journal-title":"Neuro-Oncology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1985.63.2.0155","article-title":"Intracranial germ-cell tumors: natural history and pathogenesis","volume":"63","author":"Jennings","year":"1985","journal-title":"J Neurosurg"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1997.86.3.0446","article-title":"Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases","volume":"86","author":"Matsutani","year":"1997","journal-title":"J Neurosurg"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3171\/2019.11.JNS191576","article-title":"Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo clinic and Japanese consortium cohorts","volume":"1","author":"Takami","year":"2020","journal-title":"J Neurosurg"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO classification of tumors of the central nervous system: a summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nox122","article-title":"Outcome of patients with intracranial non-germinomatous germ cell tumors\u2013lessons from the SIOP-CNS-GCT-96 trial","volume":"19","author":"Calaminus","year":"2017","journal-title":"Neuro Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/not019","article-title":"SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease","volume":"15","author":"Calaminus","year":"2013","journal-title":"Neuro Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00701","article-title":"Phase II trial of response-based radiation therapy for patients with localized CNS nongerminomatous germ cell tumors: a children's oncology group study","volume":"37","author":"Fangusaro","year":"2019","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2464","DOI":"10.1200\/JCO.2014.59.5132","article-title":"Phase II trial assessing the ability of neoadjuvant chemotherapy with or without second-look surgery to eliminate measurable disease for nongerminomatous germ cell tumors: A children's oncology group study","volume":"33","author":"Goldman","year":"2015","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab252","article-title":"EANO, SNO and euracan consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults","volume":"24","author":"Frappaz","year":"2022","journal-title":"Neuro-Oncology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab242","article-title":"The Japan society for neuro-oncology guideline on the diagnosis and treatment of central nervous system germ cell tumors","volume":"24","author":"Nakamura","year":"2022","journal-title":"Neuro-Oncology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"vdac061","DOI":"10.1093\/noajnl\/vdac061","article-title":"Still divergent but on the way to convergence: clinical practice of CNS germ cell tumors in Europe and north America from the perspectives of the East","volume":"4","author":"Takami","year":"2022","journal-title":"Neuro-Oncology Advances."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2014.12.009","article-title":"Radiation-induced malignant gliomas: a current review","volume":"83","author":"Elsamadicy","year":"2015","journal-title":"World Neurosurg"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-3019(03)00137-X","article-title":"Radiation-induced gliomas: report of 10 cases and review of the literature","volume":"60","author":"Salvati","year":"2003","journal-title":"Surg Neurol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00381-011-1390-4","article-title":"Radiation-induced tumors in children irradiated for brain tumor: a longitudinal study","volume":"27","author":"Vinchon","year":"2011","journal-title":"Childs Nerv. Syst"},{"key":"B16","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1007\/s00381-008-0631-7","article-title":"Radiation-induced brain tumours after central nervous system irradiation in childhood: a review","volume":"24","author":"Pettorini","year":"2008","journal-title":"Childs Nerv. Syst"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/neuros\/nyaa108","article-title":"Novel diagnostic methods and posttreatment clinical phenotypes among intracranial germ cell tumors","volume":"87","author":"Takami","year":"2020","journal-title":"Neurosurgery."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-005-9009-9","article-title":"Radiation induced meningioma with a short latent period following high dose cranial irradiation - case report and literature review","volume":"77","author":"Choudhary","year":"2006","journal-title":"J Neurooncol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00244-2","article-title":"Consensus on the management of intracranial germ-cell tumours","volume":"16","author":"Murray","year":"2015","journal-title":"Lancet Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2009.06.077","article-title":"Long-term follow-up of dose-adapted and reduced-field radiotherapy with or without chemotherapy for central nervous system germinoma","volume":"77","author":"Jensen","year":"2010","journal-title":"Int J Radiat Oncol Biol Physics."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2008.01.061","article-title":"Upfront chemotherapy and involved-field radiotherapy results in more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume might be needed","volume":"71","author":"Eom","year":"2008","journal-title":"Int J Radiat. Oncol Biol Phys"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab270","article-title":"Phase II trial of response-based radiation therapy for patients with localized germinoma: a children\u2019s oncology group study","volume":"24","author":"Bartels","year":"2022","journal-title":"Neuro-Oncology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2004.10.026","article-title":"CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome","volume":"62","author":"Ogino","year":"2005","journal-title":"Int J Radiat. Oncol Biol Phys"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3171\/2016.4.PEDS1658","article-title":"Human chorionic gonadotropin detection in cerebrospinal fluid of patients with a germinoma and its prognostic significance: assessment by using a highly sensitive enzyme immunoassay","author":"Fukuoka","year":"","journal-title":"J Neurosurgery: Pediatrics."},{"key":"B25","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s11060-015-1809-y","article-title":"Human chorionic gonadotropin is expressed virtually in all intracranial germ cell tumors","volume":"124","author":"Takami","year":"2015","journal-title":"J Neurooncol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.14791\/btrt.2022.10.F-1321","article-title":"Outcomes of intracranial germinoma\u2013a retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies","volume":"24","author":"Koh","year":"2022","journal-title":"Neuro-Oncology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3835(95)99394-9","article-title":"Immunohistochemical characterization of \u2018small, lymphoid-like cell populations\u2019 within germinomas: immunologic and molecular approaches to diagnosis","volume":"90","author":"Nitta","year":"1995","journal-title":"Cancer Lett"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12570","article-title":"Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance","volume":"46","author":"Takami","year":"2020","journal-title":"Neuropathol. Appl Neurobiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"vdab110","DOI":"10.1093\/noajnl\/vdab110","article-title":"Low tumor cell content predicts favorable prognosis in germinoma patients","volume":"3","author":"Takami","year":"2021","journal-title":"Neuro-Oncology Advances."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.22381","article-title":"Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study","volume":"54","author":"da Silva","year":"2010","journal-title":"Pediatr Blood cancer."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac021","article-title":"Transcriptome and methylome analysis of CNS germ cell tumor finds its cell-of-origin in embryogenesis and reveals shared similarities with testicular counterparts","volume":"24","author":"Takami","year":"2022","journal-title":"Neuro-Oncology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0178-9","article-title":"Human germ cell tumours from a developmental perspective","volume":"19","author":"Oosterhuis","year":"2019","journal-title":"Nat Rev Cancer."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s003810050469","article-title":"Surgery in the management of primary intracranial germ cell tumors","volume":"15","author":"Weiner","year":"1999","journal-title":"Childs Nerv. Syst"},{"key":"B34","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1038\/modpathol.3800607","article-title":"Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization","volume":"19","author":"Schneider","year":"2006","journal-title":"Mod Pathol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/0165-4608(96)00043-X","article-title":"Comparative genomic hybridization of germ cell tumors of the adult testis: confirmation of karyotypic findings and identification of a 12p-amplicon","volume":"89","author":"Mostert","year":"1996","journal-title":"Cancer Genet Cytogenet."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab246","article-title":"12p gain is predominantly observed in non-germinomatous germ cell tumors and identifies an unfavorable subgroup of central nervous system germ cell tumors","volume":"24","author":"Satomi","year":"2022","journal-title":"Neuro-Oncology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1007\/s00401-016-1557-x","article-title":"Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy","volume":"131","author":"Ichimura","year":"2016","journal-title":"Acta Neuropathol."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02809","article-title":"Chromosome 3p25. 3 gain is associated with cisplatin resistance and is an independent predictor of poor outcome in Male malignant germ cell tumors","volume":"2022","author":"Timmerman","year":"","journal-title":"J Clin Oncol"},{"key":"B39","doi-asserted-by":"crossref","DOI":"10.1242\/dev.02688","article-title":"Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration","volume":"133","author":"Runyan","year":"2006","journal-title":"Development"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40478-020-00953-2","article-title":"Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients","volume":"8","author":"Guntner","year":"2020","journal-title":"Acta neuropathologica Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.10392","article-title":"CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the kit-, Ras\/Raf\/Erk- and akt-pathways","volume":"7","author":"Schulte","year":"2016","journal-title":"Oncotarget."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1673-2","article-title":"Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas","volume":"133","author":"Fukushima","year":"2017","journal-title":"Acta Neuropathol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/1471-2164-11-132","article-title":"Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations","volume":"11","author":"Wang","year":"2010","journal-title":"BMC Genomics"},{"key":"B44","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1002\/path.1948","article-title":"New evidence for the origin of intracranial germ cell tumours from primordial germ cells: expression of pluripotency and cell differentiation markers","volume":"209","author":"Hoei-Hansen","year":"2006","journal-title":"J Pathol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.037","article-title":"A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors","volume":"124","author":"Voorhoeve","year":"2006","journal-title":"Cell."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1200\/JCO.18.01480","article-title":"Serum levels of microRNA-371a-3p (M371 test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study","volume":"37","author":"Dieckmann","year":"2019","journal-title":"J Clin Oncol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"vdaa048","DOI":"10.1093\/noajnl\/vdaa048","article-title":"Clinical utility of circulating miR-371a-3p for the management of patients with intracranial malignant germ cell tumors","volume":"2","author":"Murray","year":"2020","journal-title":"Neuro-Oncology Advances."}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.982608\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T05:44:53Z","timestamp":1662356693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.982608\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,5]]},"references-count":47,"alternative-id":["10.3389\/fonc.2022.982608"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.982608","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,5]]},"article-number":"982608"}}