Faculty Bibliography
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448
Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma
Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.
PMID: 32594172
ISSN: 1554-6578
CID: 4503772
Diffuse Glioneuronal tumour with Oligodendroglioma-like features and Nuclear Clusters (DGONC) - a molecularly-defined glioneuronal CNS tumour class displaying recurrent monosomy 14
AIMS/OBJECTIVE:DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly-distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterising a novel, molecularly-defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS/METHODS:DNA methylation profiling was performed using the Infinium MethylationEPIC or 450k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multi-national collaborators. Histological sections were also collected and independently reviewed. RESULTS:Genome-wide DNA methylation data from >25,000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear-cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS:DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
PMID: 31867747
ISSN: 1365-2990
CID: 4262352
International journal of environmental research & public health. 2020:17(15).DOI: 10.3390/ijerph17155493
Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster
The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.
PMID: 32751422
ISSN: 1660-4601
CID: 4553982
Molecular and clinicopathologic features of gliomas harboring NTRK fusions
Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.
PMID: 32665022
ISSN: 2051-5960
CID: 4528152
WITHDRAWN: ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS
The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.ajpath.2020.07.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
PMID: 32650002
ISSN: 1525-2191
CID: 4539692
MiR-1253 exerts tumor suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7-H3)
Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR-1253, a brain-enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR-1253 confers novel tumor-suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR-1253. We then explored the anti-tumorigenic properties of miR-1253 in parallel with a biochemical analysis of apoptosis and proliferation, and isolation of oncogenic targets using high-throughput screening. Deregulation of miR-1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de-methylation of miR-1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest, and reduction of markers of proliferation. We identified two oncogenic targets of miR-1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR-1253. These data reveal novel tumor-suppressive properties for miR-1253, i.e. 1) loss of expression via epigenetic silencing, 2) negative trophic effects on tumor aggressiveness, and 3) downregulation of oncogenic targets.
PMID: 32145124
ISSN: 1750-3639
CID: 4341002
Infant high grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes
Infant high grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histological review, methylation profiling, custom panel and genome/exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an 'intrinsic' spectrum of disease specific to the infant population. These included those with targetable MAP-kinase alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n=31), NTRK1/2/3 (n=21), ROS1 (n=9) and MET (n=4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly supports the concept that infant gliomas require a change in diagnostic practice and management.
PMID: 32238360
ISSN: 2159-8290
CID: 4370372
Tumor microenvironment is critical for the maintenance of cellular states found in primary glioblastomas
Glioblastoma, an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA-sequencing of tumor cells from five patients across four patient-specific glioblastoma stem cell (GSC)-derived model types, including glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient-derived xenografts. We find that GSCs within the GLICO model are enriched for a neural progenitor-like cell (NPC) subpopulation and recapitulate the cellular states and their plasticity found in the corresponding primary parental tumors. These data demonstrate how the contribution of a neuroanatomically accurate human microenvironment is critical and sufficient for recapitulating the cellular states found in human primary GBMs, a principle that may likely apply to other tumor models.
PMID: 32253265
ISSN: 2159-8290
CID: 4377142
Journal of neuropathology & experimental neurology. 2020:Conference:(96th):690-691.DOI: 10.1093/jnen/nlaa036
Chordoid meningiomas lacking other atypical features behave like who grade 1 meningiomas [Meeting Abstract]
Chordoid meningioma is a rare histological variant, which comprises <1% of all meningiomas. In the initially reported case series, these tumors were described to have a high recurrence rate, especially following subtotal resection, and are thus designated as WHO grade 2, according to current diagnostic criteria. However, more recent case series suggested that chordoid morphology itself, in the absence of other atypical features, did not predict more adverse outcomes, and survival paralleled that of all meningiomas. Among a cohort of 1897 meningiomas resected between 1995 and 2019, we identified 11 cases of meningioma with predominant chordoid morphology and sufficient follow up. Nine of those were otherwise WHO grade I, and only one of them recurred. The two remaining cases otherwise qualified for atypical meningioma, one of which recurred and the patient died of disease. Compared to a control cohort of 473 nonchordoid meningiomas with available follow up, chordoid meningiomas that were otherwise WHO grade 1 had progression-free and overall survival of 100%, which paralleled nonchordoid grade 1 meningiomas by Kaplan-Meier survival curve analysis. The follow up interval ranged between 31 and 219 months, with mean follow up of 108 months. Moreover, genome wide DNA methylation profiling of these 9 chordoid cases classified 8 into methylation class Ben-2 category and only 1 into methylation class Int-A category. In summary, our own institutional experience suggests that chordoid histology alone does not portend a worse prognosis. Based on the methylation and survival data, we suggest that chordoid meningiomas should be graded analogously to nonchordoid meningiomas
EMBASE:632060180
ISSN: 1554-6578
CID: 4550282
Novel EWSR1-VGLL1 fusion in a pediatric neuroepithelial neoplasm [Letter]
PMID: 31925773
ISSN: 1399-0004
CID: 4257852
