Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas.
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ABSTRACT:
SUBMITTER: Scheer M
PROVIDER: S-EPMC8745708 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.
| S-EPMC6712691 | biostudies-literature
Project description:ObjectiveTo perform a longitudinal analysis of clinical features associated with neurofibromatosis type 1 (NF1) based on demographic and clinical characteristics and to apply a machine learning strategy to determine feasibility of developing exploratory predictive models of optic pathway glioma (OPG) and attention-deficit/hyperactivity disorder (ADHD) in a pediatric NF1 cohort.MethodsUsing NF1 as a model system, we perform retrospective data analyses using a manually curated NF1 clinical registry and electronic health record (EHR) information and develop machine learning models. Data for 798 individuals were available, with 578 comprising the pediatric cohort used for analysis.ResultsMales and females were evenly represented in the cohort. White children were more likely to develop OPG (odds ratio [OR]: 2.11, 95% confidence interval [CI]: 1.11-4.00, p = 0.02) relative to their non-White peers. Median age at diagnosis of OPG was 6.5 years (1.7-17.0), irrespective of sex. Males were more likely than females to have a diagnosis of ADHD (OR: 1.90, 95% CI: 1.33-2.70, p < 0.001), and earlier diagnosis in males relative to females was observed. The gradient boosting classification model predicted diagnosis of ADHD with an area under the receiver operator characteristic (AUROC) of 0.74 and predicted diagnosis of OPG with an AUROC of 0.82.ConclusionsUsing readily available clinical and EHR data, we successfully recapitulated several important and clinically relevant patterns in NF1 semiology specifically based on demographic and clinical characteristics. Naive machine learning techniques can be potentially used to develop and validate predictive phenotype complexes applicable to risk stratification and disease management in NF1.
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Project description:Elucidation of the biological framework underlying the development of neurofibromatosis type 1 (NF1)-related symptoms has proved to be difficult. Complicating factors include the large size of the NF1 gene, the presence of several NF1 pseudogenes, the complex interactions between cell types, and the NF1-haploinsufficient state of all cells in the body. Here, we investigate three patients with distinct NF1-associated clinical manifestations (neurofibromas only, pigmentary changes only, and association of both symptoms). For each patient, various tissues and cell types were tested with comprehensive and quantitative assays capable of detecting low-percentage NF1 mutations. This approach confirmed the biallelic NF1 inactivation in Schwann cells in neurofibromas and, for the first time, demonstrated biallelic NF1 inactivation in melanocytes in NF1-related cafe-au-lait macules. Interestingly, both disease features arise even within a background of predominantly NF1 wild-type cells. Together, the data provide molecular evidence that (1) the distinct clinical picture of the patients is due to mosaicism for the NF1 mutation and (2) the mosaic phenotype reflects the embryonic timing and, accordingly, the neural crest-derived cell type involved in the somatic NF1 mutation. The study of the affected cell types provides important insight into developmental concepts underlying particular NF1-related disease features and opens avenues for improved diagnosis and genetic counseling of individuals with mosaic NF1.
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Project description:T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 1015 (ref. 1) to as high as 1061 (ref. 2) possible receptors). Despite this potential diversity, TCRs from T cells that recognize the same pMHC epitope often share conserved sequence features, suggesting that it may be possible to predictively model epitope specificity. Here we report the in-depth characterization of ten epitope-specific TCR repertoires of CD8+ T cells from mice and humans, representing over 4,600 in-frame single-cell-derived TCRαβ sequence pairs from 110 subjects. We developed analytical tools to characterize these epitope-specific repertoires: a distance measure on the space of TCRs that permits clustering and visualization, a robust repertoire diversity metric that accommodates the low number of paired public receptors observed when compared to single-chain analyses, and a distance-based classifier that can assign previously unobserved TCRs to characterized repertoires with robust sensitivity and specificity. Our analyses demonstrate that each epitope-specific repertoire contains a clustered group of receptors that share core sequence similarities, together with a dispersed set of diverse 'outlier' sequences. By identifying shared motifs in core sequences, we were able to highlight key conserved residues driving essential elements of TCR recognition. These analyses provide insights into the generalizable, underlying features of epitope-specific repertoires and adaptive immune recognition.
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Project description:MotivationThe Human Reference Epigenome Map, generated by the Roadmap Epigenomics Consortium, contains thousands of genome-wide epigenomic datasets that describe epigenomes of a variety of different human tissue and cell types. This map has allowed investigators to obtain a much deeper and more comprehensive view of our regulatory genome, e.g. defining regulatory elements including all promoters and enhancers for a given tissue or cell type. An outstanding task is to combine and compare different epigenomes in order to identify regions with epigenomic features specific to certain types of tissues or cells, e.g. lineage-specific regulatory elements. Currently available tools do not directly address this question. This need motivated us to develop a tool that allows investigators to easily identify regions with epigenetic features unique to specific epigenomes that they choose, making detection of common regulatory elements and/or cell type-specific regulatory elements an interactive and dynamic experience.ResultsAn online tool EpiCompare was developed to assist investigators in exploring the specificity of epigenomic features across selected tissue and cell types. Investigators can design their test by choosing different combinations of epigenomes, and choosing different classification algorithms provided by our tool. EpiCompare will then identify regions with specified epigenomic features, and provide a quality assessment of the predictions. Investigators can interact with EpiCompare by investigating Roadmap Epigenomics data, or uploading their own data for comparison. We demonstrate that by using specific combinations of epigenomes we can detect developmental lineage-specific enhancers. Finally, prediction results can be readily visualized and further explored in the WashU Epigenome Browser.Availability and implementationEpiCompare is freely available on the web at http://epigenome.wustl.edu/EpiCompare/.Contacttwang@genetics.wustl.edu.Supplementary informationSupplementary data are available at Bioinformatics online.
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Project description:Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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Project description:We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.
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Project description:TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). Here, we characterized the subset of IDH-wt GBMs that do not have TERTp mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH-wt GBMs, after excluding 11 IDH-mutant cases and one H3F3A -mutant case. Within the IDH-wt cases, 16 cases (14.7%) were TERTp wild-type (TERTp-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERTp-wt GBMs, were significantly younger at first diagnosis (53.2 years vs. 60.7 years, p?=?0.0096), and were more frequently found to have cerebellar location (p?=?0.0027). Notably, 9 of 16 (56%) of TERTp-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERTp-mutant GBMs harbored these alterations (p?=?0.0018). As expected, 8/16 (50%) of TERTp-wt GBMs harbored mutations in the BAF complex gene family (ATRX, SMARCA4, SMARCB1, and ARID1A), compared with only 8/93 (9%) of TERTp-mutant GBMs (p?=?0.0003). Mutations in BAF complex and PI3K pathway genes co-occurred more frequently in TERTp-wt GBMs (p?=?0.0002), an association that has been observed in other cancers, suggesting a functional interaction indicative of a distinct pathway of gliomagenesis. Overall, our finding highlights heterogeneity within WHO-defined IDH wild-type GBMs and enrichment of the TERTp-wt subset for BAF/PI3K-altered tumors, potentially comprising a distinct clinical subtype of gliomas.
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