Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.

Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1+/- ;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/- ;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology.

Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically, cell density was associated with poor progression-free and overall survival (pPFS = 0.0026, pOS < 0.01). Molecularly, tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors and were significantly enriched in cell-dense tumor areas as shown by single-cell RNA (scRNA)-sequencing as well as copy number profiling and fluorescence in situ hybridization (FISH) analyses of different tumor areas. Finally, spatial transcriptomics revealed cell-dense areas of different tumors to be more similar than various different areas of the same tumor. High-density areas distinctly overexpressed genes encoding histone proteins, WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher proportion of cell-dense areas (p = 0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors. Our data suggest that PF-EPN-A ependymomas habor a previously unrecognized intratumoral heterogeneity with clinical implications, which has to be accounted for when selecting diagnostic material, inter alia, by histological evaluation of the proportion of cell-dense areas.

Rapid DNA methylation-based classification of pediatric brain tumors from ultrasonic aspirate specimens.

BACKGROUND: Although cavitating ultrasonic aspirators are commonly used in neurosurgical procedures, the suitability of ultrasonic aspirator-derived tumor material for diagnostic procedures is still controversial. Here, we explore the feasibility of using ultrasonic aspirator-resected tumor tissue to classify otherwise discarded sample material by fast DNA methylation-based analysis using low pass nanopore whole genome sequencing. METHODS: Ultrasonic aspirator-derived specimens from pediatric patients undergoing brain tumor resection were subjected to low-pass nanopore whole genome sequencing. DNA methylation-based classification using a neural network classifier and copy number variation analysis were performed. Tumor purity was estimated from copy number profiles. Results were compared to microarray (EPIC)-based routine neuropathological histomorphological and molecular evaluation. RESULTS: 19 samples with confirmed neuropathological diagnosis were evaluated. All samples were successfully sequenced and passed quality control for further analysis. DNA and sequencing characteristics from ultrasonic aspirator-derived specimens were comparable to routinely processed tumor tissue. Classification of both methods was concordant regarding methylation class in 17/19 (89%) cases. Application of a platform-specific threshold for nanopore-based classification ensured a specificity of 100%, whereas sensitivity was 79%. Copy number variation profiles were generated for all cases and matched EPIC results in 18/19 (95%) samples, even allowing the identification of diagnostically or therapeutically relevant genomic alterations. CONCLUSION: Methylation-based classification of pediatric CNS tumors based on ultrasonic aspirator-reduced and otherwise discarded tissue is feasible using time- and cost-efficient nanopore sequencing.

Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts.

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Focal versus craniospinal radiation for disseminated atypical teratoid/rhabdoid tumor following favorable response to systemic therapy.

PURPOSE: Radiotherapy (RT) is associated with improved survival in atypical teratoid/rhabdoid tumor (ATRT); however, optimal RT delivery is unknown. A meta-analysis was conducted for disseminated (M+) ATRT receiving focal or craniospinal radiation (CSI). METHODS: After abstract screening, 25 studies (1995-2020) contained necessary patient, disease, and radiation treatment information (N = 96). All abstract, full text, and data capture were independently double-reviewed. The corresponding author was contacted for cases of insufficient information. Response to pre-radiation chemotherapy (N = 57) was categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Univariate and multivariate statistics were performed to investigate survival correlation. Patients with M4 disease were excluded. RESULTS: The 2- and 4-year overall survival (OS) was 63.8% and 45.7%, respectively, with a median follow-up of 2 years (range 0.3-13.5). The median age was 2 years (range 0.2-19.5), and 96% received chemotherapy. On univariate analysis, gross total resection (GTR, p = .0007), pre-radiation chemotherapy response (p < .001), and high-dose chemotherapy with stem cell recuse (HDSCT, p = .002) correlated with survival. On multivariate analysis, pre-radiation chemotherapy response (p = .02) and GTR (p = .012) retained survival significance as compared to a trend for HDSCT (p = .072). Comparisons of focal RT (vs. CSI) and greater than or equal to 5400 cGy primary dose were nonsignificant. Following CR or PR, a statistical trend favored focal radiation (p = .089) over CSI. CONCLUSION: Chemotherapy response prior to RT and GTR correlated with improved survival on multivariate analysis for ATRT M+ receiving RT. No benefit was observed for CSI compared to focal RT among all patients and following favorable chemotherapy response, inviting further study of focal RT for ATRT M+.

Clinical and molecular characterization of isolated M1 disease in pediatric medulloblastoma: experience from the German HIT-MED studies.

PURPOSE: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only). METHODS: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients. RESULTS: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (pPFS/OS < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01). CONCLUSIONS: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen.

Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study.

Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

ETMR: a tumor entity in its infancy.

Embryonal tumor with Multilayered Rosettes (ETMR) is a relatively rare but typically deadly type of brain tumor that occurs mostly in infants. Since the discovery of the characteristic chromosome 19 miRNA cluster (C19MC) amplification a decade ago, the methods for diagnosing this entity have improved and many new insights in the molecular landscape of ETMRs have been acquired. All ETMRs, despite their highly heterogeneous histology, are characterized by specific high expression of the RNA-binding protein LIN28A, which is, therefore, often used as a diagnostic marker for these tumors. ETMRs have few recurrent genetic aberrations, mainly affecting the miRNA pathway and including amplification of C19MC (embryonal tumor with multilayered rosettes, C19MC-altered) and mutually exclusive biallelic DICER1 mutations of which the first hit is typically inherited through the germline (embryonal tumor with multilayered rosettes, DICER1-altered). Identification of downstream pathways affected by the deregulated miRNA machinery has led to several proposed potential therapeutical vulnerabilities including targeting the WNT, SHH, or mTOR pathways, MYCN or chromosomal instability. However, despite those findings, treatment outcomes have only marginally improved, since the initial description of this tumor entity. Many patients do not survive longer than a year after diagnosis and the 5-year overall survival rate is still lower than 30%. Thus, there is an urgent need to translate the new insights in ETMR biology into more effective treatments. Here, we present an overview of clinical and molecular characteristics of ETMRs and the current progress on potential targeted therapies.

Molecular subgrouping of primary pineal parenchymal tumors reveals distinct subtypes correlated with clinical parameters and genetic alterations.

Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis.

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

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.

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series.

BACKGROUND: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. PATIENTS AND METHODS: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed. RESULTS: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. CONCLUSION: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. IMPLICATIONS FOR PRACTICE: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group.

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants.

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.

Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

Risk stratification of childhood medulloblastoma in the molecular era: the current consensus.

Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3-17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75-90 % survival), high risk (50-75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.

Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study.

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.