Faculty Bibliography
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441
Tumors of the pineal region can be classified into distinct subgroups based on molecular characteristics correlating with clinical parameters and genetic alterations [Meeting Abstract]
Several different entities with distinct clinical and histopathological features are described within in the group of pineal tumors. Whereas pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID) and papillary tumors of the pineal region (PTPR) predominantly affect adults and are associated with a relatively favorable prognosis, pineoblastoma (PB) occurs at young age and constitutes a highly aggressive tumor. Despite multimodal treatment, prognosis is poor (especially for infants and patients with metastatic disease), and therapeutically actionable molecular targets are lacking to date. Most PB arise sporadically, however, DICER1 or RB1 germline mutations are known to predispose to the development of PB, the latter in the context of trilateral retinoblastoma. Genome-wide DNA methylation profiling and copy-number analysis were used to investigate the biological features of 230 pineal tumors of different histologies. Known histopathological entities (PC, PTPR, PPTID) could be clearly separated by unsupervised clustering, as well as further distinct subgroups, including the previously hypothesized PTPR-A and PTPR-B groups. Notably, several biologically discrete subgroups were formed by the tumors initially diagnosed as PB or pineal primitive embryonal tumors/PNETs, which showed distinct clinical associations (e.g. age distribution). Somatic deletions of DROSHA, an endoribonuclease involved in miRNA processing upstream of DICER1, seem to be a recurrent feature of the largest subgroup. Rarer DICER1 and DGCR8 alterations in this group confirm a central role of altered miRNA biogenesis in the development of this subset of PB. Further molecular and functional characterization of novel sub-clusters, including ongoing miRNAseq, will provide insights into the oncogenesis of PB
EMBASE:623098745
ISSN: 1523-5866
CID: 3211272
Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP containing the ancestral DUF1220 domain in pineoblastoma [Meeting Abstract]
BACKGROUND: Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. METHODS: We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. RESULTS: Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA-and NF-kappaB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. CONCLUSION: We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma
EMBASE:623098707
ISSN: 1523-5866
CID: 3211282
PDL-1 expression on circulating CD68 (-) monocyte-like cells in NF2 meningioma as a biomarker for tumor progression [Meeting Abstract]
Program cell death ligand-1 (PD-L1) membranous expression on >5% tumor cells (PD-L1 positive tumors) is an unfavorable prognostic marker in many solid tumors. We previously showed that approximately 40% of neurofibromatosis type 2 (NF2) meningiomas are PD-L1 positive tumors. However, due to the invasive nature of biopsies, collection of tumor tissue is not always feasible. Thus, a non-invasive alternative is needed to evaluate the status of tumor growth and confirm PD-L1 positive tumors before the consideration of immunotherapy. It has recently been revealed that expression of PD-L1 on tumor associated macrophages is also a strong prognostic indicator. We retrieved formalin-fixed paraffin-embedded (FFPE) tissue from 10 NF2 meningioma cases to identify PD-L1 expression on macrophages and/or monocytes. We found that 3 out of 4 PD-L1 positive tumors were associated with expression of PDL-1 on CD68 (-) monocyte-like cells located in the peri-and intravascular lumens. These cells were only observed in 1 out of 6 PD-L1 negative tumors. Compared to others, tumors with PD-L1 expression on monocyte-like cells presented a higher Ki-67 proliferative index that was above 10%. Our results suggest that PD-L1 positive circulating CD68 (-) monocyte-like cells are correlated with tumor cell PD-L1 expression and progression in NF2 meningiomas
EMBASE:623098590
ISSN: 1523-5866
CID: 3211292
Pre-treatment monocyte-to-lymphocyte ratio in pediatric gliomas with histone H3 K27M mutation [Meeting Abstract]
We previously reported an increased prevalence of pre-treatment lymphopenia in pediatric patients with medulloblastoma, the most common childhood malignant brain tumor, suggesting tumor-induced systemic immune suppression present at the time of diagnosis. Tumor-induced systemic immune suppression, including lymphopenia, has been recognized in adult high-grade gliomas for several decades. Pediatric midline gliomas express distinct epigenetic and genetic alterations, such as the histone H3 K27M mutation. Patients with this mutation often experience a more aggressive clinical course and poor outcome. We confirmed the K27M mutation from tumor biopsies in 10 pediatric midline glioma patients by whole genome DNA methylation array analysis, and analyzed complete blood counts (CBC) at the time of diagnosis prior to surgery and chemotherapy. Compared to a control group of pilocytic astrocytoma, patients with K27M-mutated gliomas have higher monocyte-to-lymphocyte ratios (MLR) and absolute monocyte counts (AMC), reaching statistical significance (p<0.05). Furthermore, the prevalence of monocytosis, characterized by AMC above normal age-adjusted means, was statistically significantly higher (p<0.05) in the study group (80%) than the control group (33%). High pre-operative MLR has previously been reported in various solid tumors in association with worse prognosis and poor overall survival. This is the first study to our knowledge that identifies MLR as a potential valuable biomarker in pediatric gliomas. Our findings suggest monocytosis and overall tumor-induced systemic immune suppression present at the time of diagnosis in K27M mutant tumors. Aberrant circulating immune cell ratios may affect the development of immune therapies for malignant pediatric midline gliomas with the histone H3 K27M mutation
EMBASE:623098564
ISSN: 1523-5866
CID: 3211312
Pediatric meningiomas are molecularly distinct from adult counterparts [Meeting Abstract]
In contrast to adulthood, meningiomas are rare among children and adolescents. Although recent papers have characterized the genomics of adult meningiomas, the molecular profiles of childhood meningiomas have not been elucidated in detail. We analyzed 41 tumor samples from 37 pediatric meningioma patients (female: 17, male: 20; age range: 1-21 years). Atypical meningioma WHO grade II was the most frequent histological subtype (N=14, 38%). Most tumors were located at the convexity (N=18) or the skull base (N=15). Lack of SMO, AKT, KLF4/TRAF7 mutations by Sanger sequencing (n=22) prompted whole genome sequencing of a subset (n=7). All seven cases exhibited bi-allelic inactivation of NF2 (combined large deletion and germline (5/7) or somatic (2/7) base exchanges/frameshifts). Subsequently, tumor samples from all 37 patients were subjected to 450K DNA methylation profiling and targeted DNA sequencing using brain tumor specific gene panel. Loss of chromosome 22 was frequent (N=28, 76%), followed by loss of chromosome 1 (N=12, 32%) and chromosome 18 (N=7, 19%). Moreover, separation into three groups was evident: One encompassing all clear-cell meningiomas with enrichment for SMARCE1 mutations, a second dominated by atypical meningiomas, and a third group composed of benign meningiomas, as well as rare subtypes such as rhabdoid meningiomas. When analyzed with 105 adult tumors, most of pediatric meningiomas (28/37) clustered into a separate methylation group both by unsupervised hierarchical clustering and t-stochastic nearest neighbor embedding (t-SNE). Four recurrences were similar to the primary tumor. These data suggest that pediatric meningiomas are genetically distinct from adult counterparts
EMBASE:623098441
ISSN: 1523-5866
CID: 3211322
Automated cell enrichment and digital cell sorting using dielectrophoretic arrays for isolation of circulating tumor cells in pediatric brain tumor patients [Meeting Abstract]
INTRODUCTION: Liquid biopsy has the potential to revolutionize diagnosis and management of cancer. In brain tumors, detection of cell free tumor DNA (ctDNA) and circulating tumor cells (CTC) is challenging due to low level of the circulating material. We present a novel workflow for detection and capture of CTCs. METHODS: Peripheral blood was obtained from five pediatric patients with astrocytoma (n=2), ependymoma (n=1), dysembryoplastic neuroepithelial tumor (n=1), and medulloblastoma (n=1) at initial resection (n=3) and relapse (n=2). Samples were enriched using the Clear-Bridge ClearCell FX1 system and the suspension stained with antibodies against CD56 and CD45. Samples were analyzed using Silicon Biosystems DEPArray to capture single and pooled CTCs. CTCs were identified by CD56 positivity, while leukocytes were positive for CD45 and NK cells double-positive for CD56 and CD45. RESULTS: CTCs were identified in all 5 patient samples. The number of CD56-positive cells isolated from each sample ranged from 1 to 25 (mean 9). The CD56-positive cells were on average 11.8 mum in diameter (range 9.0-15.7 mum), and CD45-positive cells were on average 10.8 mum in diameter (range 8.9-15.9 mum). Single CTCs and CTC pools are amenable to molecular analysis after whole genome amplification. CONCLUSION: We report a novel integrated workflow for capturing CTCs in pediatric patients with brain tumors. While rare, CTCs circulate in peripheral blood of patients with brain tumors regardless of their grade and are amenable for molecular analysis. This method has the potential to serve as a non-invasive diagnostic and monitoring method for pediatric brain tumors
EMBASE:623098158
ISSN: 1523-5866
CID: 3211372
Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We performed immunohistochemistry for PD-L1 (clones SP142 and E1L3N), CD3, CD20, CD8, and CD68 in NF1-related tumors (ten dermal and six plexiform neurofibromas) and NF2-related tumors (ten meningiomas and ten schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with > 5% membranous staining of tumor cells, in accordance with previously published biomarker studies. PD-L1 expression in tumor cells (using the SP142 and E1L3N clones, respectively) was assessed as positive in plexiform neurofibromas (6/6 and 5/6) dermal neurofibromas (8/10 and 6/10), schwannomas (7/10 and 10/10), and meningiomas (4/10 and 2/10). Sparse to moderate presence of CD68, CD3, or CD8 positive TILs was found in 36 (100%) of tumor specimens. Our findings indicate that adaptive resistance to cell-mediated immunity may play a major role in the tumor immune microenvironment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and the presence of TILs suggest that these tumors might be responsive to immunotherapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.
PMCID:5930071
PMID: 29427150
ISSN: 1573-7373
CID: 2969022
Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis
Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin "inflammation-driven angiogenesis." We observed soluble immunosuppressive cytokines, predominantly TGF-β1, and surface integrin (αvβ3) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (αvβ3)-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (αvβ3) and cytokine receptor (TGFβ-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and altered ECM. Hence, we provide an interactive and controllable GBM tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in GBM angiogenesis, paving a new direction of screening novel anti-angiogenic therapies.
PMID: 29421553
ISSN: 1878-5905
CID: 2948312
DNA methylation-based classification of central nervous system tumours
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
PMCID:6093218
PMID: 29539639
ISSN: 1476-4687
CID: 2992882
Reclassifying Triple Negative Breast Cancers after Fluorescent In Situ Hybridization for Human Epidermal Growth Factor Receptor 2 [Meeting Abstract]
ISI:000429308600325
ISSN: 0893-3952
CID: 3049092
