Project description:Ependymal tumors across age groups have been classified solely by histopathology. It is, however, commonly accepted that this classification has limited clinical utility based on its poor reliability. We aimed at establishing a reliable and reproducible molecular classification using DNA methylation fingerprints of the tumors. Studying a cohort of 500 tumors allowed for the delineation of nine robust molecular subgroups, three in each anatomic compartment of the central nervous system (CNS). Two of the supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification by far and thus might serve as a basis for the upcoming update of the WHO classification of CNS tumors. DNA methylation patterns in tumors have been shown to represent a very stable molecular memory of the respective cell of origin throughout the disease course, thus making them particularly suitable for tumor classification purposes. Methylation fingerprinting of a large series of ependymal tumors of all grades revealed a highly reliable way of classifying this clinically extremely heterogeneous group of malignancies. In fact, out of nine highly reproducible molecular subgroups identified in the supratentorial, infratentorial and spinal regions, only two harbor the vast majority of clinical high-risk patients (mostly children) for whom novel therapeutic concepts are desperately needed. Since this analysis can be performed from minute amounts of DNA extracted from archived material, it is ideally suited for routine clinical application. We investigated a set of 562 ependymal tumors using the Illumina 450k methylation array.
Project description:Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
Project description:Ependymal tumors across age groups have been classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patient outcome. We aimed at establishing a reliable molecular classification using DNA methylation fingerprints and gene expression data of the tumors on a large cohort of 500 tumors. Nine robust molecular subgroups, three in each anatomic compartment of the central nervous system (CNS), were identified. Total RNA from 209 ependymal tumor samples were hybridised to the Affymetrix HG U133 Plus 2.0 microarrays.
Project description:Ependymal tumors across age groups have been classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patient outcome. We aimed at establishing a reliable molecular classification using DNA methylation fingerprints and gene expression data of the tumors on a large cohort of 500 tumors. Nine robust molecular subgroups, three in each anatomic compartment of the central nervous system (CNS), were identified.
Project description:Meningiomas account for roughly one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular groups that reliably predicted clinical severity. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular group as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, resulting in cell cycle activation, and only tumors in this group tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.
Project description:Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of CNS tumors in children under 3 years (Bouffet et al., 2009; McGuire et al., 2009; Rodriguez et al., 2009). In children, most ependymomas arise in the posterior fossa, while most adult ependymomas present around the lower spinal cord and spinal nerve roots. Ependymomas display a wide range of morphological features, and several variants are listed in the World Health Organization (WHO) classification (Ellison et al., 2016). These variants are assigned to three WHO grades (I-III), but the clinical utility of this classification is acknowledged to be limited (Ellison et al., 2011). An increasing understanding of the genomic landscape of ependymoma and the discovery of distinct molecular groups by DNA methylation or gene expression profiling have begun to refine approaches to disease classification and prognostication, but have yet to be translated into clinical routine (Hoffman et al., 2014; Mack et al., 2014; Pajtler et al., 2017; Pajtler et al., 2015; Parker et al., 2014; Wani et al., 2012; Witt et al., 2011). Our comprehensive study of DNA methylation profiling across the entire disease demonstrated three molecular groups for each major anatomic compartment: supratentorial (ST), posterior fossa (PF), and spinal (SP) (Pajtler et al., 2015). In the ST compartment, two molecular groups (ST-EPN-RELA and ST-EPN-YAP1) align with tumors harboring specific genetic alterations, RELA and YAP1 fusion genes, which were initially discovered in a whole genome sequencing study (Parker et al., 2014). Among PF ependymomas, two of three molecular groups, PFA (PF-EPN-A) and PFB (PF-EPN-B), account for nearly all tumors; PF-SE tumors are rare, generally showing the morphology of a subependymoma (Pajtler et al., 2015). PFA tumors are found mainly in infants and young children (median age ≈ 3yrs) and have a relatively poor outcome, while PFB tumors are generally found in young adults (median age ≈ 30yrs) and are associated with a better prognosis (Pajtler et al., 2015; Witt et al., 2011). PFA tumors show few copy number alterations (CNAs), while PFB tumors harbor multiple CNAs that tend to affect entire chromosomes. While recurrent structural variants (SVs) are found in ST ependymomas, recurrent SVs or other mutations, such as single nucleotide variants (SNVs) and insertions or deletions (indels), have not been identified in PF ependymomas to date (Mack et al., 2014; Parker et al., 2014).
Project description:Tumors of the central nervous system are the most common solid neoplasia during human childhood, representing one of the leading causes of cancer-related mortality. Tumors that originate from astrocyte cells (astrocytoma) in the brain are the most frequently found. According to their histological and pathological features, these tumors are classified into four categories. However, recently an extra layer of molecular classification of the tumorigenesis-associated genes IDH1/2 and H3F3A has been incorporated into the classification guidelines. While mutations in H3F3A are exclusively found in a subtype of pediatric astrocytoma grade IV, mutations in IDH1/2 are very rare in children younger than 14 years old. The transcriptomic profiles of astrocytoma in adults and children have been extensively studied however focusing on the study of the transcriptomic profile of the different grades of astrocytoma (including the additional layer of molecular classification) in pediatric populations are scarce. Therefore, we have profiled the transcriptomic landscape of the four grades of pediatric astrocytoma by RNA sequencing.
Project description:Molecular profiling of cerebral gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification and IDH1/2 mutation status. We performed microarray-based genome- and transcriptome-wide molecular profiling of primary tumor samples from 137 patients with cerebral gliomas, 61 WHO grade II and 76 WHO grade III tumors. For this study, we screened prospectively recruited patients with a histopathological reference diagnosis of cerebral tumors of WHO grade II and III, known KPS at diagnosis, information on extent of resection by early postoperative neuroimaging, available frozen tissue specimens from the initial operation, and documented clinical outcome.
Project description:Meningiomas are common brain tumors that are classified into three World Health Organization grades (Grade I: benign, Grade II: atypical and Grade III: malignant) and are molecularly ill-defined tumors. The purpose of this study was identify microRNA (miRNA) molecular signatures unique to the different grades of meningiomas correlating them to prognosis. We have used a miRNA expression microarray to show that meningiomas of all three grades fall into two main molecular groups designated “benign” and “malignant” meningiomas. While all typical meningiomas fall into the benign group and all anaplastic meningiomas fall into the malignant group, atypical meningiomas distribute into either one of these groups. We have identified a miRNA signature that distinguishes benign meningiomas from malignant meningiomas.
Project description:Primitive neuroectodermal tumors of the central nervous system (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children. Using DNA methylation and gene expression profiling we have demonstrated that a significant proportion of institutionally diagnosed CNS PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumor entities, facilitating diagnosis and appropiate therapy for children with these tumors. From the remaining fraction of CNS PNETs, we have identified four distinct new CNS tumor entities extending to other neuroepithelial tumors, each associated with a recurrent genetic alteration and particular histopathological and clinical features. These molecular entities, designated âCNS Neuroblastoma with FOXR2 activation (CNS NB FOXR2)â, âCNS Ewing sarcoma family tumor with CIC alteration (CNS EFT CIC)â, âCNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET MN1)â, and âCNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET BCOR)â, will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by these poorly differentiated CNS tumors. 182 brain tumor samples were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays.