Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1 , the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% ( n = 7) and 11% ( n = 4) of the recurrences ( n = 38) as compared to 7% ( n = 3) and 0% ( n = 0) in the primary tumors ( n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.

Pediatric Blood & CancerEarly View e29594 LETTER TO THE EDITOR ALK inhibition as a salvage therapy for a relapsed unclassifiable sarcomatous CNS tumor with EML4/ALK fusion in an infant Till Holsten, Till Holsten orcid.org/0000-0001-7933-1141 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorAnnika Bronsema, Annika Bronsema Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorDominik Sturm, Dominik Sturm Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany Pediatric Glioma Research, Germany Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, GermanySearch for more papers by this authorFelix Sahm, Felix Sahm Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, Heidelberg, GermanySearch for more papers by this authorStefan Rutkowski, Stefan Rutkowski Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorUlrich Schüller, Ulrich Schüller Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Research Institute Children's Cancer Center Hamburg, Hamburg, Germany Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorWilhelm Wößmann, Wilhelm Wößmann Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorUwe R. Kordes, Corresponding Author Uwe R. Kordes kordes@uke.de orcid.org/0000-0001-6375-2320 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence Uwe R. Kordes, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, O 47, D-20251 Hamburg, Germany. Email: kordes@uke.deSearch for more papers by this author Till Holsten, Till Holsten orcid.org/0000-0001-7933-1141 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorAnnika Bronsema, Annika Bronsema Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorDominik Sturm, Dominik Sturm Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany Pediatric Glioma Research, Germany Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, GermanySearch for more papers by this authorFelix Sahm, Felix Sahm Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, Heidelberg, GermanySearch for more papers by this authorStefan Rutkowski, Stefan Rutkowski Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorUlrich Schüller, Ulrich Schüller Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Research Institute Children's Cancer Center Hamburg, Hamburg, Germany Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorWilhelm Wößmann, Wilhelm Wößmann Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorUwe R. Kordes, Corresponding Author Uwe R. Kordes kordes@uke.de orcid.org/0000-0001-6375-2320 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence Uwe R. Kordes, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, O 47, D-20251 Hamburg, Germany. Email: kordes@uke.deSearch for more papers by this author First published: 23 February 2022 https://doi.org/10.1002/pbc.29594Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Rhabdoid tumors (RT) are embryonal neoplasms occurring most frequently in the central nervous system where they are termed atypical teratoid rhabdoid tumor (ATRT). A common hallmark of RT is homozygous loss of the BAF complex subunit SMARCB1. RT patients have a poor prognosis with an overall survival time of 17 months and >60% of patients suffer from relapses. The lack of an optimal treatment strategy could be attributed to the heterogeneity within and between different subgroups of ATRT. Despite the recent advancements in characterizing RT at a molecular level, the cellular origin of RT remains elusive. Thus, this study focused on the identification of the cellular origin of MYC-RT and underlying epigenetic deregulations which account for the cellular heterogeneity in these tumors. We showed that Smarcb1 abrogation in Sox2-positive progenitor cells at E6.5 give rise to RT of the MYC and SHH subgroup in genetically engineered mouse models (GEMM). To uncover distinct cells of origin (COO) for the SHH and MYC subgroups, unbiased computational approaches were used to compare single-cell transcriptomes of GEMMs with single-cell reference maps of murine early embryogenesis. While SHH tumors arise from mid/hindbrain progenitor cells, primordial germ cells (PGCs) emerge as COO of both intracranial and extracranial MYC tumors. PGCs as COO of MYC-RT were validated in vivo by using PGC-specific Smarcb1 knockout mouse model. We further characterized a deregulated transcriptome in MYC-RT compared to PGCs, which is sustained by a subset of epigenetically driven tumor cells. Deregulated expression of genes driving methylation/demethylation processes in MYC tumors and regression of these tumors upon treatment with decitabine in vitro and in vivo, indicates that DNA methylation plays a key role in cellular transformation and development of MYC-RT.

Central nervous system neuroblastoma with FOXR2 activation (CNS NB FOXR2) has recently been described as a class of brain tumors sharing common genetic events and a highly similar DNA methylation profile. Most of these tumors have previously been diagnosed as primitive neuroectodermal tumor (PNET). Whereas the entity of PNET has been removed from the WHO classification of brain tumors in its current edition, CNS neuroblastoma was kept as an entity, but still lacks any molecular detail. Here, we describe 8 cases of CNS NB FOXR2 focusing on histomorphological and immunohistochemical features and include magnetic resonance imaging (MRI) for 2 of these cases. MRI revealed large supratentorial masses in superficial location with prominent cysts and necrosis, but little edema. Diffusion and enhancement characteristics were variable. Histological analyses showed that most of the cases displayed neuronal differentiation with necrosis, endothelial proliferation, and high vascularity. Immunohistochemistry revealed strong expression of synaptophysin, MAP2, and OLIG2 as well as moderate proliferation. These findings suggest that tumors with the molecular diagnosis of CNS NB FOXR2 may fit well into the WHO entity of CNS neuroblastoma. Our findings may be helpful when establishing an integrated diagnosis and may be indispensable if molecular data are unavailable.

Medulloblastoma (MB) is the most frequent malignant brain tumour in children with a poor outcome. Divided into four molecular subgroups, MB of the Sonic hedgehog (SHH) subgroup accounts for approximately 25% of the cases and is driven by mutations within components of the SHH pathway, such as its receptors PTCH1 or SMO. A fraction of these cases additionally harbour PIK3CA mutations, the relevance of which is so far unknown. To unravel the role of Pik3ca mutations alone or in combination with a constitutively activated SHH signalling pathway, transgenic mice were used. These mice show mutated variants within Smo, Ptch1 or Pik3ca genes in cerebellar granule neuron precursors, which represent the cellular origin of SHH MB. Our results show that Pik3ca mutations alone are insufficient to cause developmental alterations or to initiate MB. However, they significantly accelerate the growth of Shh MB, induce tumour spread throughout the cerebrospinal fluid, and result in lower survival rates of mice with a double Pik3caH1047R/SmoM2 or Pik3caH1047R/Ptch1 mutation. Therefore, PIK3CA mutations in SHH MB may represent a therapeutic target for first and second line combination treatments.

The molecular biology of ependymomas is not well understood and this is particularly true for ependymoma relapses. We aimed at finding out if and to which extent, relapses differ from their corresponding primary tumors on the morphological, chromosomal and epigenetic level. We investigated 24 matched ependymoma primary and relapsed tumor samples and, as a first step, compared cell density, necrosis, vessel proliferation, Ki67 proliferative index, trimethylation at H3K27 and expression of CXorf67. For the investigation of global methylation profiles, we used public data in order to analyze copy number variation profiles, differential methylation, methylation status and fractions of hypo- and hypermethylated CpGs in different epigenomic substructures. Morphologically, we found a significant increase with relapse in cell density and proliferation. H3K27 trimethylation and CXorf67 expression remained stable between primary and relapse tumor samples, and the analysis of DNA methylation profiles neither revealed significant differences in copy number variations nor differentially methylated regions. Significant differences in the methylation status were found for CpG islands, but also in N Shelves or S Shelves, depending on the molecular subgroup. The fraction of probes changing their methylation in the epigenomic substructures appeared subgroup-specific. Most changes occur in CpG islands, for which relapsed tumors demonstrate higher methylation values than primary tumors. The morphological differences reflect increased aggressiveness upon ependymoma relapse, but, despite slight changes, this observation does not appear to be sufficiently explained by epigenetic changes.

Glycogen storage disease (GSD) 0a is a rare congenital metabolic disease with symptoms in infancy and childhood caused by biallelic GYS2 germline variants. A predisposition to cancer has not been described yet. We report here a boy with GSD 0a, who developed a malignant brain tumor at the age of 4.5 years. The tumor was classified as a group 3 medulloblastoma, and the patient died from cancer 27 months after initial tumor diagnosis. This case appears interesting as group 3 medulloblastoma is so far not known to arise in hereditary syndromes and the biology of sporadic group 3 medulloblastoma is largely unknown.

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.

Germline mutations affecting the SWI/SNF chromatin remodeling complex are associated with a broad spectrum of different diseases, including malignant and benign tumors as well as neurodevelopmental disorders. Such mutations are detected in multiple genes of the complex and encompass a variety of mutation types. However, due to the rarity of mutation carriers, very little is known about the impact of specific SWI/SNF mutations on the phenotype of the affected individual. In this meta-analysis, we link genetic and clinical data from more than 400 families and more than 500 patients affected by SWI/SNF germline alterations, including over 40 so far unpublished patients. Here we demonstrate that large deletions and truncating mutations of a gene tend to be associated with malignancy and early-onset-disease, while non-truncating mutations may cause non-malignant disorders, such as Coffin-Siris-syndrome or late onset tumors like Schwannomas or Meningiomas (p=<0.0001). Importantly, germline SWI/SNF mutations may also be detected in healthy relatives, although this does not hold true for families with whole gene deletions. Our data may have important implications for genetic counseling of affected families and will pave the way for functional mutation analyses that may improve the understanding of SWI/SNF-related disorders.

Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds. Combination of both compounds efficiently represses antiapoptotic genes and the oncogene MYC. Our results provide a novel approach for the treatment of RT.

Neuroblastoma (NBL) stage 4s is an incompletely understood phenomenon with variable clinical course. While the majority of patients may undergo spontaneous regression and achieve complete resolution without intensive therapy, a small proportion is at increased risk of developing secondary complications. One such situation is liver insufficiency due to diffuse metastases. We report a patient suffering from NBL 4S who required double lifesaving liver transplantation. Abdominal and respiratory complications due to hepatomegaly are crucial determinants for treatment intensity and duration in 4S NBL [1,2] . We provide an algorithm in order to facilitate the clinical decision when dealing with similar potentially life-threatening events.

Rhabdoid tumors are highly aggressive tumors occurring in infants and very young children. Despite multimodal and intensive therapy prognosis remains poor. Molecular analyses have uncovered several deregulated pathways, among them the CDK4/6‐Rb‐, the WNT‐ and the Sonic hedgehog (SHH) pathways. The SHH pathway is activated in rhabdoid tumors by GLI1 overexpression. Here, we demonstrate that arsenic trioxide (ATO) inhibits tumor cell growth of malignant rhabdoid tumors in vitro and in a mouse xenograft model by suppressing Gli1. Our data uncover ATO as a promising therapeutic approach to improve prognosis for rhabdoid tumor patients.

BACKGROUND: To describe therapeutic approaches in children with atypical Teratoid Rhabdoid Tumours (ATRT) in France.METHODS: Observational study including all children less than 18 years old diagnosed with ATRT in France between 2009 and 2011.RESULTS: Forty seven children were included in this retrospective study.Six patients received no curative treatment while forty-one patients had a curative project.Median age was 1.5 years (range 0-16).The disease was disseminated in 10 patients.Surgical resection was complete in 21 cases.Chemotherapy was administered in 41 children.Twenty-six patients received upfront Vincristine-Methotrexate (5g/m 2 x 3) with intra-thecal Methotrexate, which was stopped in eleven patients: in four cases the disease progressed and in seven cases the toxicities were manageable.Fifteen children received different chemotherapy courses and in four of them the diseases progressed.Eight patients underwent second-look surgery.Radiotherapy was administered in 17 patients at a median time of 19 weeks (13-44) after diagnosis.High-dose chemotherapy (HDCT) was given in 9 children and maintenance therapy in 5 children, starting at respectively 35 and 42 weeks after diagnosis.Median follow-up was 26 months (0.6-47).Median time for progression was 5 months.Two-years overall survival was 32% + /-8%.Median survival was 8 months.DISCUSSION: The survival rate of children with ATRT remains poor, the addition of VM is easily manageable but its benefit remains uncertain.The disease progressed mostly before radiotherapy.Future trials should focus on the delay of radiotherapy and the benefit of HDCT.

Rhabdoid tumors are rare but highly aggressive tumors with a predilection for infants and young children. The majority of these tumors harbor biallelic mutations in SMARCB1/INI1/hSNF5. Rather rare cases with mutations in other SWI/SNF core members such as BRG1 are on record. Rhabdoid tumors have only recently been registered and treated according to specifically designed treatment recommendations and in the framework of clinical trials. Within the last decade, prognosis has improved significantly but at least 50% of patients still relapse and subsequently almost inevitably succumb to their disease. This review summarizes past and current clinical approaches and presents an overview of the rationales for targeted therapy with potential for future clinical treatment trials for rhabdoid tumors.

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.