Publications by authors named "Pascal Johann"

52 Publications

Cui Bono? Identifying Patient Groups That May Benefit From Granulocyte Transfusions in Pediatric Hematology and Oncology.

J Pediatr Hematol Oncol 2021 Oct 26. Epub 2021 Oct 26.

Hopp Children's Cancer Center (KiTZ) DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center Department of Pediatric Oncology, Hematology and Immunology, Hopp Children's Cancer Center Heidelberg (KiTZ), University of Heidelberg, Heidelberg Swabian Childrens' Cancer Center, University Childrens' Hospital Augsburg and EU-RHAB Registry, Augsburg Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg-Hessen, Medical Faculty Mannheim, Heidelberg University, Mannheim Department of Pediatric Hematology and Oncology, Clinic of Pediatrics III, University Hospital Essen, Essen, Germany.

Introduction: Granulocyte transfusions have long been used to bridge the time to neutrophil recovery in patients with neutropenia and severe infection. Recent randomized controlled trials did not prove a beneficial effect of granulocyte transfusions, but were likely underpowered and suffered from very heterogeneous study populations.

Methods: We retrospectively reviewed data of all patients treated with granulocyte transfusions at our pediatric center from 2004 to 2019. In order to identify parameters that predict the success of granulocyte transfusions, we stratified patients in 3 groups. Patients in group 1 cleared their infection, whereas patients in group 2 succumbed to an infection in neutropenia despite granulocyte transfusions. A third group included all patients who died of causes that were not related to infection.

Results: We demonstrate that patients without respiratory or cardiocirculatory insufficiency are enriched in group 1 and more likely to benefit from granulocyte transfusions than patients who already require these intensive care measures. The effect of granulocyte transfusions correlates with the cell dose per body weight applied per time. With our standard twice weekly dosing, patients with a body weight below 40 kg are more likely to achieve a sufficient leukocyte increment and clear their infection in comparison to patients with a higher body weight.

Discussion/conclusions: We suggest that future studies on the benefits of granulocyte transfusions stratify patients according to clinical risk factors that include the need for respiratory or cardiocirculatory support and strive for a sufficient dose density of granulocyte transfusions.
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http://dx.doi.org/10.1097/MPH.0000000000002349DOI Listing
October 2021

Treatment and outcome of intracranial ependymoma after first relapse in AIEOP 2 nd protocol.

Neuro Oncol 2021 Oct 4. Epub 2021 Oct 4.

Neurology and Psichiatry Department of La Sapienza University, Rome, Italy.

Background: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2 nd AIEOP protocol.

Methods: We considered relapse sites and treatments ,i.e. various combinations of complete/incomplete surgery, if followed by standard or hypo-fractionated radiation(RT) ± chemotherapy(CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses.

Results: The median follow-up was 147 months after diagnosis, 84 after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse(LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse.

Conclusions: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well posed, randomized questions could clarify the numerous issues, orient salvage treatment and ameliorate prognosis for this group of patients.
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http://dx.doi.org/10.1093/neuonc/noab230DOI Listing
October 2021

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

J Immunother Cancer 2021 10;9(10)

University Children's Hospital, University Medical Center Würzburg, Würzburg, Germany

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.

Methods: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.

Results: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8 T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.

Conclusions: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
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http://dx.doi.org/10.1136/jitc-2021-003404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488729PMC
October 2021

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

Cancer Discov 2021 Nov 9;11(11):2764-2779. Epub 2021 Aug 9.

Department of Pediatric Oncology and Hematology, University Hospital Magdeburg, Magdeburg, Germany.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes...
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http://dx.doi.org/10.1158/2159-8290.CD-21-0094DOI Listing
November 2021

Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors.

Pediatr Blood Cancer 2021 Dec 4;68(12):e29267. Epub 2021 Aug 4.

University Medical Center Augsburg, Paediatric and Adolescent Medicine, Swabian Children's Cancer Center, Augsburg, Germany.

Background: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly.

Materials And Methods: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available.

Results: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders.

Conclusions: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.
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http://dx.doi.org/10.1002/pbc.29267DOI Listing
December 2021

IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies: Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome.

Am J Surg Pathol 2021 09;45(9):1190-1204

Departments of Neuropathology.

IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.
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http://dx.doi.org/10.1097/PAS.0000000000001697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373679PMC
September 2021

The drug development pipeline for glioblastoma-A cross sectional assessment of the FDA Orphan Drug Product designation database.

PLoS One 2021 7;16(7):e0252924. Epub 2021 Jul 7.

Paediatric Neurology and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Background: Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest.

Objectives: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM.

Methods: Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected.

Results: Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline.

Conclusion: Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263276PMC
October 2021

Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.

Acta Neuropathol 2021 08 18;142(2):361-374. Epub 2021 May 18.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.
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http://dx.doi.org/10.1007/s00401-021-02328-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270878PMC
August 2021

Histopathological patterns in atypical teratoid/rhabdoid tumors are related to molecular subgroup.

Brain Pathol 2021 09 3;31(5):e12967. Epub 2021 May 3.

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor that may not only contain rhabdoid tumor cells but also poorly differentiated small-round-blue cells as well as areas with mesenchymal or epithelial differentiation. Little is known on factors associated with histopathological diversity. Recent studies demonstrated three molecular subgroups of AT/RT, namely ATRT-TYR, ATRT-SHH, and ATRT-MYC. We thus aimed to investigate if morphological patterns might be related to molecular subgroup status. Hematoxylin-eosin stained sections of 114 AT/RT with known molecular subgroup status were digitalized and independently categorized by nine blinded observers into four morphological categories, that is, "rhabdoid," "small-round-blue," "epithelial," and "mesenchymal." The series comprised 48 ATRT-SHH, 40 ATRT-TYR, and 26 ATRT-MYC tumors. Inter-observer agreement was moderate but significant (Fleiss' kappa = 0.47; 95% C.I. 0.41-0.53; p < 0.001) and there was a highly significant overall association between morphological categories and molecular subgroups for each of the nine observers (p < 0.0001). Specifically, the category "epithelial" was found to be over-represented in ATRT-TYR (p < 0.000001) and the category "small-round-blue" to be over-represented in ATRT-SHH (p < 0.01). The majority of ATRT-MYC was categorized as "mesenchymal" or "rhabdoid," but this association was less compelling. The specificity of the category "epithelial" for ATRT-TYR was highest and accounted for 97% (range: 88-99%) whereas sensitivity was low [49% (range: 35%-63%)]. In line with these findings, cytokeratin-positivity was highly overrepresented in ATRT-TYR. In conclusion, morphological features of AT/RT might reflect molecular alterations and may also provide a first hint on molecular subgroup status, which will need to be confirmed by DNA methylation profiling.
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http://dx.doi.org/10.1111/bpa.12967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412123PMC
September 2021

Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma.

Am J Surg Pathol 2021 09;45(9):1228-1234

Institute of Neuropathology.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.
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http://dx.doi.org/10.1097/PAS.0000000000001694DOI Listing
September 2021

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

Clin Cancer Res 2021 May 18;27(10):2879-2889. Epub 2021 Mar 18.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.

Materials And Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; = 52) and children (SJMB03: age 3-21 years; = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.

Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR ( = 21), SHH ( = 30), and MYC ( = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. GLAs were not associated with PFS.

Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127412PMC
May 2021

Sarcoma classification by DNA methylation profiling.

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases.

Acta Neuropathol 2021 02 17;141(2):291-301. Epub 2020 Dec 17.

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

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.
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http://dx.doi.org/10.1007/s00401-020-02250-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847432PMC
February 2021

Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up.

Neuro Oncol 2021 05;23(5):848-857

Departments of Neurology and Psychiatric, La Sapienza University, Rome, Italy.

Background: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features.

Methods: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68.

Results: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007).

Conclusions: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.
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http://dx.doi.org/10.1093/neuonc/noaa257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099475PMC
May 2021

Novel Two MRT Cell Lines Established from Multiple Sites of a Synchronous MRT Patient.

Anticancer Res 2020 Nov;40(11):6159-6170

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Background/aim: Malignant rhabdoid tumor (MRT) is a rare, aggressive neoplasm found in young children, caused by inactivation of a single gene, SNF5 (INI1, SMARCB1). MRT cases with multifocal tumors at diagnosis are categorized as synchronous MRT, often with a germline mutation of SNF5. The aim of this study was to establish new models useful in clarifying the biological basis of synchronous MRT.

Materials And Methods: We established two novel MRT cell lines, designated as KP-MRT-KS and KP-MRT-KSa, derived from different lesions and at a different time from a synchronous multifocal 7-month-old female MRT patient.

Results: Both cells showed typical morphology of MRT, with a compound genomic mutation in exons 2 and 5 of the SNF5 gene. The exon 2 mutation was found in the germline.

Conclusion: These cell lines could serve as powerful tools for unveiling the molecular mechanism of refractory synchronous MRT.
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http://dx.doi.org/10.21873/anticanres.14636DOI Listing
November 2020

SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability.

Genes Dev 2020 10 10;34(19-20):1316-1329. Epub 2020 Sep 10.

Ludwig Institute for Cancer Research, La Jolla, California 92093, USA.

Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene , a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.
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http://dx.doi.org/10.1101/gad.339978.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528703PMC
October 2020

A single supratentorial high-grade neuroepithelial tumor with two distinct BCOR mutations, exceptionally long complete remission and survival.

Pediatr Blood Cancer 2020 07 8;67(7):e28384. Epub 2020 May 8.

Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.

Here, we present a patient with high-grade neuroepithelial tumors with mutations in the BCL6 corepressor BCOR (HGNET-BCOR), a rare, highly malignant brain tumor with poor prognosis. The patient underwent gross total tumor resection (GTR), high-dose chemotherapy, and, after local relapse, GTR, proton radiation, and chemotherapy. After a 7.5 year-long complete remission, the tumor recurred locally, was treated by GTR, and responded to temozolomide treatment. In addition to an internal tandem duplication in BCOR common to the majority of HGNET-BCOR cases, molecular analysis revealed a second BCOR mutation in this tumor: a frame shift mutation. The combination of these mutations was associated with relatively low BCOR expression compared to other HGNET-BCOR cases.
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http://dx.doi.org/10.1002/pbc.28384DOI Listing
July 2020

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Nat Med 2020 05 27;26(5):712-719. Epub 2020 Apr 27.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. ), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
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http://dx.doi.org/10.1038/s41591-020-0821-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992505PMC
May 2020

Molecular subgrouping of atypical teratoid/rhabdoid tumors-a reinvestigation and current consensus.

Neuro Oncol 2020 05;22(5):613-624

Hopp Children's Cancer Center, Heidelberg, Germany.

Background: Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event present in nearly all cases. Indeed, recent studies demonstrated 3 molecular subgroups of ATRTs that are genetically, epigenetically, and clinically distinct. As these studies included different numbers of tumors, various subgrouping techniques, and naming, an international working group sought to align previous findings and to reach a consensus on nomenclature and clinicopathological significance of ATRT subgroups.

Methods: We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data.

Results: In concordance with previous studies, the analyses identified 3 main molecular subgroups of ATRTs, for which a consensus was reached to name them ATRT-TYR, ATRT-SHH, and ATRT-MYC. The ATRT-SHH subgroup exhibited further heterogeneity, segregating further into 2 subtypes associated with a predominant supratentorial (ATRT-SHH-1) or infratentorial (ATRT-SHH-2) location. For each ATRT subgroup we provide an overview of its main molecular and clinical characteristics, including SMARCB1 alterations and pathway activation.

Conclusions: The introduction of a common classification, characterization, and nomenclature of ATRT subgroups will facilitate future research and serve as a common ground for subgrouping patient samples and ATRT models, which will aid in refining subgroup-based therapies for ATRT patients.
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http://dx.doi.org/10.1093/neuonc/noz235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229260PMC
May 2020

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors.

Neuro Oncol 2020 07;22(7):1006-1017

Department of Pediatric Hematology and Oncology, University of Würzburg, Würzburg, Germany.

Background: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses.

Methods: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors.

Results: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%).

Conclusions: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.
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http://dx.doi.org/10.1093/neuonc/noz244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339901PMC
July 2020

Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients.

Pediatr Blood Cancer 2020 02 18;67(2):e28074. Epub 2019 Nov 18.

Division of Pediatric Stem Cell Transplant and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Pediatric histiocytic sarcoma (HS) clonally related to anteceding leukemia is a rare malignancy with poor outcome. We performed a molecular characterization of HS and the corresponding leukemia by methylation arrays and whole-exome sequencing and found a variety of aberrations in both entities with deletions of CDKN2A/B as a recurrent finding. Furthermore, data from genome-wide mutation analysis from one patient allowed the reconstruction of a sequence of tumorigenesis of leukemia and HS lesions including the acquisition of a putatively activating KRAS frameshift deletion (p.A66fs). Our results provide an insight into the genetic landscape of pediatric HS clonally related to anteceding leukemia.
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http://dx.doi.org/10.1002/pbc.28074DOI Listing
February 2020

Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults.

Acta Neuropathol 2020 02 16;139(2):277-286. Epub 2019 Nov 16.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, Münster, Germany.

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
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http://dx.doi.org/10.1007/s00401-019-02094-wDOI Listing
February 2020

Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration.

Cell Rep 2019 11 7;29(8):2338-2354.e7. Epub 2019 Nov 7.

Hopp Children's Cancer Center, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.
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http://dx.doi.org/10.1016/j.celrep.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905433PMC
November 2019

RF_Purify: a novel tool for comprehensive analysis of tumor-purity in methylation array data based on random forest regression.

BMC Bioinformatics 2019 Aug 16;20(1):428. Epub 2019 Aug 16.

Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: With the advent of array-based techniques to measure methylation levels in primary tumor samples, systematic investigations of methylomes have widely been performed on a large number of tumor entities. Most of these approaches are not based on measuring individual cell methylation but rather the bulk tumor sample DNA, which contains a mixture of tumor cells, infiltrating immune cells and other stromal components. This raises questions about the purity of a certain tumor sample, given the varying degrees of stromal infiltration in different entities. Previous methods to infer tumor purity require or are based on the use of matching control samples which are rarely available. Here we present a novel, reference free method to quantify tumor purity, based on two Random Forest classifiers, which were trained on ABSOLUTE as well as ESTIMATE purity values from TCGA tumor samples. We subsequently apply this method to a previously published, large dataset of brain tumors, proving that these models perform well in datasets that have not been characterized with respect to tumor purity .

Results: Using two gold standard methods to infer purity - the ABSOLUTE score based on whole genome sequencing data and the ESTIMATE score based on gene expression data- we have optimized Random Forest classifiers to predict tumor purity in entities that were contained in the TCGA project. We validated these classifiers using an independent test data set and cross-compared it to other methods which have been applied to the TCGA datasets (such as ESTIMATE and LUMP). Using Illumina methylation array data of brain tumor entities (as published in Capper et al. (Nature 555:469-474,2018)) we applied this model to estimate tumor purity and find that subgroups of brain tumors display substantial differences in tumor purity.

Conclusions: Random forest- based tumor purity prediction is a well suited tool to extrapolate gold standard measures of purity to novel methylation array datasets. In contrast to other available methylation based tumor purity estimation methods, our classifiers do not need a priori knowledge about the tumor entity or matching control tissue to predict tumor purity.
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http://dx.doi.org/10.1186/s12859-019-3014-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697926PMC
August 2019

Excessive Toxicity After Treatment of Congenital Acute Myeloid Leukemia.

Klin Padiatr 2019 11 18;231(6):291-293. Epub 2019 Mar 18.

Department of Pediatric Hematology, Oncology and Immunology, Children's Hospital, UniversitatsKlinikum Heidelberg, Heidelberg.

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http://dx.doi.org/10.1055/a-0859-7375DOI Listing
November 2019

Comprehensive Analysis of Chromatin States in Atypical Teratoid/Rhabdoid Tumor Identifies Diverging Roles for SWI/SNF and Polycomb in Gene Regulation.

Cancer Cell 2019 01 27;35(1):95-110.e8. Epub 2018 Dec 27.

Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.
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http://dx.doi.org/10.1016/j.ccell.2018.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341227PMC
January 2019

Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors.

J Neurooncol 2019 Jan 16;141(1):43-55. Epub 2018 Nov 16.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.

Purpose: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.

Methods: The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.

Results: Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.

Conclusions: These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT.
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http://dx.doi.org/10.1007/s11060-018-03018-6DOI Listing
January 2019

Magnetic resonance imaging surrogates of molecular subgroups in atypical teratoid/rhabdoid tumor.

Neuro Oncol 2018 11;20(12):1672-1679

Reference Center for Neuroradiology, Institute for Diagnostic and Interventional Neuroradiology, University Hospital of Würzburg, Würzburg, Germany.

Background: Recently, 3 molecular subgroups of atypical teratoid/rhabdoid tumor (ATRT) were identified, but little is known of their clinical and magnetic resonance imaging (MRI) characteristics.

Methods: A total of 43 patients with known molecular subgroup status (ATRT-sonic hedgehog [SHH], n = 17; ATRT-tyrosine [TYR], n = 16; ATRT-myelocytomatosis oncogene [MYC], n = 10) were retrieved from the EU-RHAB Registry and analyzed for clinical and MRI features.

Results: On MRI review, differences in preferential tumor location were confirmed, with ATRT-TYR being predominantly located infratentorially (P < 0.05). Peritumoral edema was more pronounced in ATRT-MYC compared with ATRT-SHH (P < 0.05) and ATRT-TYR (P < 0.05). Conversely, peripheral tumor cysts were found more frequently in ATRT-SHH (71%) and ATRT-TYR (94%) compared with ATRT-MYC (40%, P < 0.05). Contrast enhancement was absent in 29% of ATRT-SHH (0% of ATRT-TYR; 10% of ATRT-MYC; P < 0.05), and there was a trend toward strong contrast enhancement in ATRT-TYR and ATRT-MYC. We found the characteristic (bandlike) enhancement in 28% of ATRT as well as restricted diffusion in the majority of tumors. A midline/off-midline location in the posterior fossa was also not subgroup specific. Visible meningeal spread (M2) at diagnosis was rare throughout all subgroups.

Conclusion: These exploratory findings suggest that MRI features vary across the 3 molecular subgroups of ATRT. Within future prospective trials, MRI may aid diagnosis and treatment stratification.
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http://dx.doi.org/10.1093/neuonc/noy111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231209PMC
November 2018
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