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05.05.2018 | Original Paper

DNA methylation-based reclassification of olfactory neuroblastoma

verfasst von: David Capper, Nils W. Engel, Damian Stichel, Matt Lechner, Stefanie Glöss, Simone Schmid, Christian Koelsche, Daniel Schrimpf, Judith Niesen, Annika K. Wefers, David T. W. Jones, Martin Sill, Oliver Weigert, Keith L. Ligon, Adriana Olar, Arend Koch, Martin Forster, Sebastian Moran, Oscar M. Tirado, Miguel Sáinz-Jaspeado, Jaume Mora, Manel Esteller, Javier Alonso, Xavier Garcia del Muro, Werner Paulus, Jörg Felsberg, Guido Reifenberger, Markus Glatzel, Stephan Frank, Camelia M. Monoranu, Valerie J. Lund, Andreas von Deimling, Stefan Pfister, Rolf Buslei, Julika Ribbat-Idel, Sven Perner, Volker Gudziol, Matthias Meinhardt, Ulrich Schüller

Erschienen in: Acta Neuropathologica | Ausgabe 2/2018

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Abstract

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1–4, 8–10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.

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Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S, Kitano Y et al (2005) CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res 65:828–834PubMed

Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA et al (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073. https://doi.org/10.1038/nature09534 CrossRefPubMed

Abedalthagafi MS, Merrill PH, Bi WL, Jones RT, Listewnik ML, Ramkissoon SH et al (2014) Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5. Oncotarget 5:10596–10606. https://doi.org/10.18632/oncotarget.2517 CrossRefPubMedPubMedCentral

Argani P, Perez-Ordonez B, Xiao H, Caruana SM, Huvos AG, Ladanyi M (1998) Olfactory neuroblastoma is not related to the Ewing family of tumors: absence of EWS/FLI1 gene fusion and MIC2 expression. Am J Surg Pathol 22:391–398CrossRefPubMed

Bockmuhl U, You X, Pacyna-Gengelbach M, Arps H, Draf W, Petersen I (2004) CGH pattern of esthesioneuroblastoma and their metastases. Brain Pathol 14:158–163CrossRefPubMed

Bridge JA, Bowen JM, Smith RB (2010) The small round blue cell tumors of the sinonasal area. Head Neck Pathol 4:84–93. https://doi.org/10.1007/s12105-009-0158-6 CrossRefPubMedPubMedCentral

Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474. https://doi.org/10.1038/nature26000 CrossRefPubMedPubMedCentral

Carney ME, O’Reilly RC, Sholevar B, Buiakova OI, Lowry LD, Keane WM et al (1995) Expression of the human Achaete-scute 1 gene in olfactory neuroblastoma (esthesioneuroblastoma). J Neurooncol 26:35–43CrossRefPubMed

Cha S, Lee J, Shin JY, Kim JY, Sim SH, Keam B et al (2016) Clinical application of genomic profiling to find druggable targets for adolescent and young adult (AYA) cancer patients with metastasis. BMC Cancer 16:170. https://doi.org/10.1186/s12885-016-2209-1 CrossRefPubMedPubMedCentral

10.

Cha S, Lee S-H, Kim J-I, Shin J-Y (2014) Abstract 4191: Whole exome sequencing of a case of olfactory neuroblastoma. Cancer Res 74:4191. https://doi.org/10.1158/1538-7445.am2014-4191 CrossRef

11.

Cohen ZR, Marmor E, Fuller GN, DeMonte F (2002) Misdiagnosis of olfactory neuroblastoma. Neurosurg Focus 12:e3CrossRefPubMed

12.

Cordes B, Williams MD, Tirado Y, Bell D, Rosenthal DI, Al-Dhahri SF et al (2009) Molecular and phenotypic analysis of poorly differentiated sinonasal neoplasms: an integrated approach for early diagnosis and classification. Hum Pathol 40:283–292. https://doi.org/10.1016/j.humpath.2008.07.019 CrossRefPubMedPubMedCentral

13.

Dogan S, Chute DJ, Xu B, Ptashkin RN, Chandramohan R, Casanova-Murphy J et al (2017) Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas. J Pathol 242:400–408. https://doi.org/10.1002/path.4915 CrossRefPubMedPubMedCentral

14.

Dong C, Wei P, Jian X, Gibbs R, Boerwinkle E, Wang K et al (2015) Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet 24:2125–2137. https://doi.org/10.1093/hmg/ddu733 CrossRefPubMed

15.

Engel NW, Neumann JE, Ahlfeld J, Wefers AK, Merk DJ, Ohli J et al (2016) Canonical Wnt signaling drives tumor-like lesions from Sox2-positive precursors of the murine olfactory epithelium. PLoS ONE 11:e0166690. https://doi.org/10.1371/journal.pone.0166690 CrossRefPubMedPubMedCentral

16.

Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159. https://doi.org/10.1056/NEJMra072067 CrossRefPubMed

17.

Faragalla H, Weinreb I (2009) Olfactory neuroblastoma: a review and update. Adv Anat Pathol 16:322–331. https://doi.org/10.1097/PAP.0b013e3181b544cf CrossRefPubMed

18.

Ferreira HJ, Heyn H, Vizoso M, Moutinho C, Vidal E, Gomez A et al (2016) DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia. Oncogene 35:3079–3082. https://doi.org/10.1038/onc.2015.359 CrossRefPubMed

19.

Gay LM, Kim S, Fedorchak K, Kundranda M, Odia Y, Nangia C et al (2017) Comprehensive genomic profiling of esthesioneuroblastoma reveals additional treatment options. Oncologist. https://doi.org/10.1634/theoncologist.2016-0287 CrossRefPubMedPubMedCentral

20.

Guled M, Myllykangas S, Frierson HF Jr, Mills SE, Knuutila S, Stelow EB (2008) Array comparative genomic hybridization analysis of olfactory neuroblastoma. Mod Pathol 21:770–778. https://doi.org/10.1038/modpathol.2008.57 CrossRefPubMed

21.

Hafezi S, Seethala RR, Stelow EB, Mills SE, Leong IT, MacDuff E et al (2011) Ewing’s family of tumors of the sinonasal tract and maxillary bone. Head Neck Pathol 5:8–16. https://doi.org/10.1007/s12105-010-0227-x CrossRefPubMed

22.

Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R et al (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916. https://doi.org/10.1007/s00401-013-1126-5 CrossRefPubMedPubMedCentral

23.

Hughes LA, Melotte V, de Schrijver J, de Maat M, Smit VT, Bovee JV et al (2013) The CpG island methylator phenotype: what’s in a name? Cancer Res 73:5858–5868. https://doi.org/10.1158/0008-5472.can-12-4306 CrossRefPubMed

24.

Hyams V (1988) Tumors of the upper respiratory tract and ear. In: Hyams V, Batsakis J, Michaelis L (eds) Atlas of tumor pathology. Armed Forces Institute of Pathology, Washington, DC, pp 240–248

25.

Iezzoni JC, Mills SE (2005) “Undifferentiated” small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol 124(Suppl):S110–S121PubMed

26.

Jo VY, Chau NG, Hornick JL, Krane JF, Sholl LM (2017) Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. Mod Pathol 30:650–659. https://doi.org/10.1038/modpathol.2016.239 CrossRefPubMed

27.

Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V et al (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393. https://doi.org/10.1016/j.ccell.2016.02.001 CrossRefPubMed

28.

Kumar S, Perlman E, Pack S, Davis M, Zhang H, Meltzer P et al (1999) Absence of EWS/FLI1 fusion in olfactory neuroblastomas indicates these tumors do not belong to the Ewing’s sarcoma family. Hum Pathol 30:1356–1360CrossRefPubMed

29.

Lazo de la Vega L, McHugh JB, Cani AK, Kunder K, Walocko FM, Liu CJ et al (2017) Comprehensive molecular profiling of olfactory neuroblastoma identifies potentially targetable FGFR3 amplifications. Mol Cancer Res. https://doi.org/10.1158/1541-7786.mcr-17-0135 PubMedCrossRef

30.

López-Hernández A, Vivanco B, Franchi A, Bloemena E, Cabal VN, Potes S et al (2018) Genetic profiling of poorly differentiated sinonasal tumours. Sci Rep 8:3998. https://doi.org/10.1038/s41598-018-21690-6 CrossRefPubMedPubMedCentral

31.

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1 CrossRefPubMed

32.

Meyer C, Hamersley ER, Manosalva RE, Torske K, McIntyre N, Mitchell A (2017) Olfactory neuroblastoma with divergent differentiation: an unusual histologic finding in a rare tumor. Head Neck Pathol. https://doi.org/10.1007/s12105-017-0781-6 PubMedPubMedCentralCrossRef

33.

Mills SE (2002) Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol 15:264–278. https://doi.org/10.1038/modpathol.3880522 CrossRefPubMed

34.

Mills SE, Fechner RE (1989) “Undifferentiated” neoplasms of the sinonasal region: differential diagnosis based on clinical, light microscopic, immunohistochemical, and ultrastructural features. Semin Diagn Pathol 6:316–328PubMed

35.

Mitchell EH, Diaz A, Yilmaz T, Roberts D, Levine N, DeMonte F et al (2012) Multimodality treatment for sinonasal neuroendocrine carcinoma. Head Neck 34:1372–1376. https://doi.org/10.1002/hed.21940 CrossRefPubMed

36.

Montone KT (2015) The differential diagnosis of sinonasal/nasopharyngeal neuroendocrine/neuroectodermally derived tumors. Arch Pathol Lab Med 139:1498–1507. https://doi.org/10.5858/arpa.2014-0383-RA CrossRefPubMed

37.

Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522. https://doi.org/10.1016/j.ccr.2010.03.017 CrossRefPubMedPubMedCentral

38.

Ow TJ, Bell D, Kupferman ME, Demonte F, Hanna EY (2013) Esthesioneuroblastoma. Neurosurg Clin N Am 24:51–65. https://doi.org/10.1016/j.nec.2012.08.005 CrossRefPubMed

39.

Pajtler KW, Witt H, Sill M, Jones DTW, Hovestadt V, Kratochwil F et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743. https://doi.org/10.1016/j.ccell.2015.04.002 CrossRefPubMedPubMedCentral

40.

Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol J Comput Mol Cell Biol 4:311–323. https://doi.org/10.1089/cmb.1997.4.311 CrossRef

41.

Rettig EM, D’Souza G (2015) Epidemiology of head and neck cancer. Surg Oncol Clin N Am 24:379–396. https://doi.org/10.1016/j.soc.2015.03.001 CrossRefPubMed

42.

Riazimand SH, Brieger J, Jacob R, Welkoborsky HJ, Mann WJ (2002) Analysis of cytogenetic aberrations in esthesioneuroblastomas by comparative genomic hybridization. Cancer Genet Cytogenet 136:53–57CrossRefPubMed

43.

Soldatova L, Campbell RG, Carrau RL, Prevedello DM, Wakely P Jr, Otto BA et al (2016) Sinonasal carcinomas with neuroendocrine features: histopathological differentiation and treatment outcomes. J Neurol Surg Part B Skull Base 77:456–465. https://doi.org/10.1055/s-0036-1582432 CrossRef

44.

Sorensen PH, Wu JK, Berean KW, Lim JF, Donn W, Frierson HF et al (1996) Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma. Proc Natl Acad Sci USA 93:1038–1043CrossRefPubMed

45.

Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072. https://doi.org/10.1016/j.cell.2016.01.015 CrossRefPubMedPubMedCentral

46.

Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437. https://doi.org/10.1016/j.ccr.2012.08.024 CrossRefPubMed

47.

Su SY, Bell D, Hanna EY (2014) Esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma: differentiation in diagnosis and treatment. Int Arch Otorhinolaryngol 18:S149–S156. https://doi.org/10.1055/s-0034-1390014 CrossRefPubMedPubMedCentral

48.

Sugita Y, Kusano K, Tokunaga O, Mineta T, Abe M, Harada H et al (2006) Olfactory neuroepithelioma: an immunohistochemical and ultrastructural study. Neuropathology 26:400–408CrossRefPubMed

49.

Taxy JB, Bharani NK, Mills SE, Frierson HF Jr, Gould VE (1986) The spectrum of olfactory neural tumors. A light-microscopic immunohistochemical and ultrastructural analysis. Am J Surg Pathol 10:687–695CrossRefPubMed

50.

Thompson LD (2009) Olfactory neuroblastoma. Head Neck Pathol 3:252–259. https://doi.org/10.1007/s12105-009-0125-2 CrossRefPubMedPubMedCentral

51.

Thompson LDR, Seethala RR, Müller S (2012) Ectopic sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary gland: a clinicopathologic and immunophenotypic study of 32 cases with a comprehensive review of the English literature. Head Neck Pathol 6:75–100. https://doi.org/10.1007/s12105-012-0336-9 CrossRefPubMedPubMedCentral

52.

Topcagic J, Feldman R, Ghazalpour A, Swensen J, Gatalica Z, Vranic S (2018) Comprehensive molecular profiling of advanced/metastatic olfactory neuroblastomas. PLoS ONE 13:e0191244. https://doi.org/10.1371/journal.pone.0191244 CrossRefPubMedPubMedCentral

53.

Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa J-PJ (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci 96:8681–8686. https://doi.org/10.1073/pnas.96.15.8681 CrossRefPubMed

54.

Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483. https://doi.org/10.1038/nature10866 CrossRefPubMedPubMedCentral

55.

van der Maaten L, Hinton G (2008) Visualizing high-dimensional data using t-SNE. J Mach Learn Res 9:2579–2605

56.

Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P et al (2012) High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov 2:82–93. https://doi.org/10.1158/2159-8290.CD-11-0184 CrossRefPubMed

57.

Weinreb I, Perez-Ordoñez B (2007) Non-small cell neuroendocrine carcinoma of the sinonasal tract and nasopharynx. Report of 2 cases and review of the literature. Head Neck Pathol 1:21–26. https://doi.org/10.1007/s12105-007-0004-7 CrossRefPubMedPubMedCentral

58.

Weiss GJ, Liang WS, Izatt T, Arora S, Cherni I, Raju RN et al (2012) Paired tumor and normal whole genome sequencing of metastatic olfactory neuroblastoma. PLoS ONE 7:e37029. https://doi.org/10.1371/journal.pone.0037029 CrossRefPubMedPubMedCentral

59.

Wenig BM (2009) Undifferentiated malignant neoplasms of the sinonasal tract. Arch Pathol Lab Med 133:699–712. https://doi.org/10.1043/1543-2165-133.5.699 PubMedCrossRef

60.

Wenig BM, Dulguerov P, Kapadia SB, Prasad ML, Fanburg-Smith JC, Thompson LDR (2005) Chapter 1: Tumours of the nasal cavity and paranasal sinuses. neuroectodermal tumors. Olfactory neuroblastoma. In: Barnes L, Eveson J, Reichart P, Sidransky D (eds) Pathology & genetics of head and neck tumours, vol 9, 3rd edn. IARC Press, Lyon, pp 66–70

61.

Wilm A, Aw PP, Bertrand D, Yeo GH, Ong SH, Wong CH et al (2012) LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res 40:11189–11201. https://doi.org/10.1093/nar/gks918 CrossRefPubMedPubMedCentral

Titel: DNA methylation-based reclassification of olfactory neuroblastoma
verfasst von: David Capper
Nils W. Engel
Damian Stichel
Matt Lechner
Stefanie Glöss
Simone Schmid
Christian Koelsche
Daniel Schrimpf
Judith Niesen
Annika K. Wefers
David T. W. Jones
Martin Sill
Oliver Weigert
Keith L. Ligon
Adriana Olar
Arend Koch
Martin Forster
Sebastian Moran
Oscar M. Tirado
Miguel Sáinz-Jaspeado
Jaume Mora
Manel Esteller
Javier Alonso
Xavier Garcia del Muro
Werner Paulus
Jörg Felsberg
Guido Reifenberger
Markus Glatzel
Stephan Frank
Camelia M. Monoranu
Valerie J. Lund
Andreas von Deimling
Stefan Pfister
Rolf Buslei
Julika Ribbat-Idel
Sven Perner
Volker Gudziol
Matthias Meinhardt
Ulrich Schüller
Publikationsdatum: 05.05.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 2/2018
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1854-7

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