Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

Asklepios Kinderklinik Sankt Augustin Sankt Augustin Germany

Department of Neuropathology Institute for Pathology University of Würzburg 97080 Würzburg Germany

Department of Neuropathology Regensburg University Hospital Regensburg Germany

Department of Neuropathology University Giessen Giessen Germany

Department of Neuropathology University Magdeburg Magdeburg Germany

Department of Neuropathology University of Bonn Medical Centre Bonn Germany

Department of Paediatrics and Adolescent Medicine University of Copenhagen Copenhagen Denmark

Department of Pathology Aarhus University Hospital Aarhus Denmark

Department of Pathology and Laboratory Medicine Children's Hospital Los Angeles Los Angeles CA USA

Department of Pathology McGill University Montreal QC Canada

Department of Pathology Rigshospitalet Copenhagen Denmark

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Oncology 2nd Department of Pediatrics Semmelweis University Budapest Hungary

Division of Anatomical Pathology Neuropathology Specialty Group Department of Laboratory Medicine and Pathology University of Alberta Edmonton Canada

Division of Paediatric Neurooncology German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Institute of Human Genetics Ulm University and Ulm University Medical Center Ulm Germany

Institute of Neuropathology University Hospital Münster Pottkamp 2 48149 Münster Germany

Institute of Neuropathology University of Duisburg Essen Essen Germany

Pediatric and Adolescent Medicine Swabian Childrens' Cancer Center University Childrens' Hospital Medical Center Augsburg and EU RHAB Registry Augsburg Germany

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

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Aydin B, Kakumanu A, Rossillo M, et al. Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes. Nat Neurosci. 2019;22:897–908. doi: 10.1038/s41593-019-0399-y. PubMed DOI PMC

Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555:469–474. doi: 10.1038/nature26000. PubMed DOI PMC

Capper D, Stichel D, Sahm F, et al. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathol. 2018;136:181–210. doi: 10.1007/s00401-018-1879-y. PubMed DOI PMC

Chen J, Wu X, Xing Z, et al. FOXG1 expression is elevated in glioma and inhibits glioma cell apoptosis. J Cancer. 2018;9:778–783. doi: 10.7150/jca.22282. PubMed DOI PMC

Cheng Y, Sudarov A, Szulc KU, et al. The Engrailed homeobox genes determine the different foliation patterns in the vermis and hemispheres of the mammalian cerebellum. Development. 2010;137:519–529. doi: 10.1242/dev.027045. PubMed DOI PMC

Cho HJ, Park HY, Kim K, et al. Methylation and molecular profiles of ependymoma: influence of patient age and tumor anatomic location. Mol Clin Oncol. 2021;14:88. doi: 10.3892/mco.2021.2250. PubMed DOI PMC

Crossley PH, Martinez S, Martin GR. Midbrain development induced by FGF8 in the chick embryo. Nature. 1996;380:66–68. doi: 10.1038/380066a0. PubMed DOI

Danesin C, Peres JN, Johansson M, et al. Integration of telencephalic Wnt and hedgehog signaling center activities by Foxg1. Dev Cell. 2009;16:576–587. doi: 10.1016/j.devcel.2009.03.007. PubMed DOI

Drummond DL, Cheng CS, Selland LG, et al. The role of Zic transcription factors in regulating hindbrain retinoic acid signaling. BMC Dev Biol. 2013;13:31. doi: 10.1186/1471-213X-13-31. PubMed DOI PMC

Frühwald MC, Biegel JA, Bourdeaut F, et al. Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies. Neuro Oncol. 2016;18:764–778. doi: 10.1093/neuonc/nov264. PubMed DOI PMC

Frühwald MC, Hasselblatt M, Nemes K, et al. Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors. Neuro Oncol. 2020;22:1006–1017. doi: 10.1093/neuonc/noz244. PubMed DOI PMC

Gu Z, Schlesner M, Hübschmann D. Cola: an R/Bioconductor package for consensus partitioning through a general framework. Nucleic Acids Res. 2021;49:e15. doi: 10.1093/nar/gkaa1146. PubMed DOI PMC

Guillemot F, Hassan BA. Beyond proneural: emerging functions and regulations of proneural proteins. Curr Opin Neurobiol. 2017;42:93–101. doi: 10.1016/j.conb.2016.11.011. PubMed DOI

Hartl TA, Scott MP. Wing tips: the wing disc as a platform for studying Hedgehog signaling. Methods. 2014;68:199–206. doi: 10.1016/j.ymeth.2014.02.002. PubMed DOI

Hasselblatt M, Isken S, Linge A, et al. High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosomes Cancer. 2013;52:185–190. doi: 10.1002/gcc.22018. PubMed DOI

Ho B, Johann PD, Grabovska Y, et al. Molecular subgrouping of atypical teratoid/rhabdoid tumors-a reinvestigation and current consensus. Neuro Oncol. 2020;22:613–624. doi: 10.1093/neuonc/noz235. PubMed DOI PMC

Hooper JE, Scott MP. Communicating with Hedgehogs. Nat Rev Mol Cell Biol. 2005;6:306–317. doi: 10.1038/nrm1622. PubMed DOI

Jagani Z, Mora-Blanco EL, Sansam CG, et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med. 2010;16:1429–1433. doi: 10.1038/nm.2251. PubMed DOI PMC

Jeibmann A, Eikmeier K, Linge A, et al. Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster. Nat Commun. 2014;5:4005. doi: 10.1038/ncomms5005. PubMed DOI

Johann PD, Erkek S, Zapatka M, et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 2016;29:379–393. doi: 10.1016/j.ccell.2016.02.001. PubMed DOI

Joyner AL, Herrup K, Auerbach BA, et al. Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science. 1991;251:1239–1243. doi: 10.1126/science.1672471. PubMed DOI

Kordes U, Gesk S, Frühwald MC, et al. Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer. 2010;49:176–181. doi: 10.1002/gcc.20729. PubMed DOI

Lambert SR, Witt H, Hovestadt V, et al. Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma. Acta Neuropathol. 2013;126:291–301. doi: 10.1007/s00401-013-1124-7. PubMed DOI

Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23:1231–1251. doi: 10.1093/neuonc/noab106. PubMed DOI PMC

Marshall CAG, Novitch BG, Goldman JE. Olig2 directs astrocyte and oligodendrocyte formation in postnatal subventricular zone cells. J Neurosci. 2005;25:7289–7298. doi: 10.1523/JNEUROSCI.1924-05.2005. PubMed DOI PMC

Nambirajan A, Gurung N, Suri V, et al. C19MC amplification and expression of Lin28A and Olig2 in the classification of embryonal tumors of the central nervous system: a 14-year retrospective study from a tertiary care center. Childs Nerv Syst. 2021;37:1067–1075. doi: 10.1007/s00381-020-04973-0. PubMed DOI

Nemes K, Bens S, Bourdeaut F, et al. et al. Rhabdoid tumor predisposition syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al.et al., editors. GeneReviews®. Seattle (WA): University of Washington; 1993. PubMed

Nowak J, Nemes K, Hohm A, et al. Magnetic resonance imaging surrogates of molecular subgroups in atypical teratoid/rhabdoid tumor. Neuro Oncol. 2018;20:1672–1679. doi: 10.1093/neuonc/noy111. PubMed DOI PMC

Pajtler KW, Wen J, Sill M, et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 2018;136:211–226. doi: 10.1007/s00401-018-1877-0. PubMed DOI PMC

Pajtler KW, Witt H, Sill M, et al. Molecular Classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27:728–743. doi: 10.1016/j.ccell.2015.04.002. PubMed DOI PMC

Perreault S, Ramaswamy V, Achrol AS, et al. MRI surrogates for molecular subgroups of medulloblastoma. AJNR Am J Neuroradiol. 2014;35:1263–1269. doi: 10.3174/ajnr.A3990. PubMed DOI PMC

Priesterbach-Ackley LP, Boldt HB, Petersen JK, et al. Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool. Neuropathol Appl Neurobiol. 2020;46:478–492. doi: 10.1111/nan.12610. PubMed DOI PMC

Pristerà A, Lin W, Kaufmann A-K, et al. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice. Proc Natl Acad Sci USA. 2015;112:E4929–E4938. doi: 10.1073/pnas.1503911112. PubMed DOI PMC

Reddy AT, Strother DR, Judkins AR, et al. Efficacy of high-dose chemotherapy and three-dimensional conformal radiation for atypical teratoid/rhabdoid tumor: a report from the children’s oncology group trial ACNS0333. J Clin Oncol. 2020;38:1175–1185. doi: 10.1200/JCO.19.01776. PubMed DOI PMC

Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56–65. doi: 10.3171/jns.1996.85.1.0056. PubMed DOI

Saj A, Arziman Z, Stempfle D, et al. A combined ex vivo and in vivo RNAi screen for notch regulators in Drosophila reveals an extensive notch interaction network. Dev Cell. 2010;18:862–876. doi: 10.1016/j.devcel.2010.03.013. PubMed DOI

Sugimori M, Nagao M, Parras CM, et al. Ascl1 is required for oligodendrocyte development in the spinal cord. Development. 2008;135:1271–1281. doi: 10.1242/dev.015370. PubMed DOI

Teo W-Y, Shen J, Su JMF, et al. Implications of tumor location on subtypes of medulloblastoma. Pediatr Blood Cancer. 2013;60:1408–1410. doi: 10.1002/pbc.24511. PubMed DOI

Torchia J, Golbourn B, Feng S, et al. Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell. 2016;30:891–908. doi: 10.1016/j.ccell.2016.11.003. PubMed DOI PMC

Torchia J, Picard D, Lafay-Cousin L, et al. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol. 2015;16:569–582. doi: 10.1016/S1470-2045(15)70114-2. PubMed DOI

Ueda R, Yoshida K, Kawakami Y, et al. Immunohistochemical analysis of SOX6 expression in human brain tumors. Brain Tumor Pathol. 2004;21:117–120. doi: 10.1007/BF02482186. PubMed DOI

Uittenbogaard M, Baxter KK, Chiaramello A. NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network. J Neurosci Res. 2010;88:33–54. doi: 10.1002/jnr.22182. PubMed DOI PMC

Xia N, Zhang P, Fang F, et al. Transcriptional comparison of human induced and primary midbrain dopaminergic neurons. Sci Rep. 2016;6:20270. doi: 10.1038/srep20270. PubMed DOI PMC

Yang J, Yang Q. Identification of core genes and screening of potential targets in glioblastoma multiforme by integrated bioinformatic analysis. Front Oncol. 2020;10:615976. doi: 10.3389/fonc.2020.615976. PubMed DOI PMC

Yu F, Fu W-M. Identification of differential splicing genes in gliomas using exon expression profiling. Mol Med Report. 2015;11:843–850. doi: 10.3892/mmr.2014.2775. PubMed DOI PMC

Zin F, Cotter JA, Haberler C, et al. Histopathological patterns in atypical teratoid/rhabdoid tumors are related to molecular subgroup. Brain Pathol. 2021;31:e12967. doi: 10.1111/bpa.12967. PubMed DOI PMC