We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Gliomas, the most common malignant primary brain tumours, remain universally lethal. Yet, seminal discoveries in the past 5 years have clarified the anatomy, genetics and function of the immune system within the central nervous system (CNS) and altered the paradigm for successful immunotherapy. The impact of standard therapies on the response to immunotherapy is now better understood, as well. This new knowledge has implications for a broad range of tumours that develop within the CNS. Nevertheless, the requirements for successful therapy remain effective delivery and target specificity, while the dramatic heterogeneity of malignant gliomas at the genetic and immunological levels remains a profound challenge.

Brain immunology and immunotherapy in brain tumours

Next-generation sequencing has identified mutations in the PRRT2 (proline-rich transmembrane protein 2) gene as the leading cause for a wide and yet evolving spectrum of paroxysmal diseases. PRRT2 mutations are found in the majority of patients with benign familial infantile epilepsy, infantile convulsions and choreoathetosis and paroxysmal kinesigenic dyskinesia, confirming a common disease spectrum that had previously been suggested based on gene linkage analyses and shared clinical features. Beyond these clinical entities, PRRT2 mutations have been described in other childhood-onset movement disorders, different forms of seizures, headache disorders, and intellectual disability. PRRT2 encodes a protein that is expressed in the central nervous system and is thought to be involved in the modulation of synaptic neurotransmitter release. The vast majority of mutations lead to a truncated protein or no protein at all and thus to a haploinsufficient state. The subsequent reduction of PRRT2 protein may lead to altered synaptic neurotransmitter release and dysregulated neuronal excitability in various regions of the brain, resulting in paroxysmal movement disorders and seizure phenotypes. In this review, we examine the genetics and neurobiology of PRRT2 and summarize the evolving clinical and molecular spectrum of PRRT2-associated diseases. Through a comprehensive review of 1444 published cases, we provide a detailed assessment of the demographics, disease characteristics and genetic findings of patients with PRRT2 mutations. Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n = 206) constitute the vast majority of PRRT2-associated diseases, leaving 76 patients (5.3%) with a different primary diagnosis. A positive family history is present in 89.1% of patients; and PRRT2 mutations are familial in 87.1% of reported cases. Seventy-three different disease-associated PRRT2 mutations (35 truncating, 22 missense, three extension mutations, six putative splice site changes, and seven changes that lead to a complete PRRT2 deletion) have been described to date, with the c.649dupC frameshift mutation accounting for the majority of cases (78.5%). Expanding the genetic landscape, 15 patients with biallelic PRRT2 mutations and six patients with 16p11.2 microdeletions and a paroxysmal kinesigenic dyskinesia phenotype have been reported. Probing the phenotypic boundaries of PRRT2-associated disorders, several movement, seizure and headache disorders have been linked to PRRT2 mutations in a subset of patients. Of these, hemiplegic migraine emerges as a novel PRRT2-associated phenotype. With this comprehensive review of PRRT2-associated diseases, we hope to provide a scientific resource for informing future research, both in laboratory models and in clinical studies.

/pdf/the-evolving-spectrum-of-prrt2-associated-paroxysmal-1wfjeiovcg.pdf

The evolving spectrum of PRRT2-associated paroxysmal diseases.

1. Basic Aspects 2. Molecular Diagnostics in Personalized Medicine 3. Role of Biomarkers in Personalized Medicine 4. Pharmacogenetics 5. Pharmacogenomics 6. Pharmacoproteomics 7. Role of Metabolomics in Personalized Medicine 8. Non-genomic Factors in the Development of Personalized Medicine 9. Personalized Biological Therapies 10. Personalized Therapy of Cancer 11. Personalized Management of Infectious Diseases 12. Personalized Management of Neurological Disorders 13. Personalized Management of Psychiatric Disorders 14. Personalized Management of Cardiovascular Disorders 15. Personalized Management of Pulmonary Disorders 16. Personalized Management of Genetic Disorders 17. Personalized Approaches to Immune Disorders 18. Personalized Approaches to Miscellaneous Problems in Healthcare 19. Personalized Non-Pharmacological Therapies 20. Development of Personalized Medicine 21. Ethical Aspects of Personalized Medicine 22. Regulatory Aspects of Personalized Medicine 23. Economics of Personalized Medicine 24. Future of Personalized Medicine

Textbook of Personalized Medicine

Astrocytic gliomas are the most common and lethal form of intracranial tumors. These tumors are characterized by a significant heterogeneity in terms of cytopathological, transcriptional, and (epi)genomic features. This heterogeneity has made these cancers one of the most challenging types of cancers to study and treat. To uncover these complexities and to have better understanding of the disease initiation and progression, identification, and characterization of underlying cellular and molecular pathways related to (epi)genetics of astrocytic gliomas is crucial. Here, we discuss and summarize molecular and (epi)genetic mechanisms that provide clues as to the pathogenesis of astrocytic gliomas. (Figure presented.). Â© 2018 International Society for Neurochemistry

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14616

Genetic and epigenetic contribution to astrocytic gliomas pathogenesis

Aims Altered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development, and lncRNA FOXD1-AS1 (FOXD1-AS1) is the antisense transcript of the gene encoding for FOXD1, known for its role as an oncogene in several tumor types including glioma. However, the role of FOXD1-AS1 in the differentiation and progression of glioma is not well known. Methods Expression profile chip and qPCR were used to screen and identify FOXD1-AS1. Glioma cells were transfected with siRNA or eukaryotic expression vector to observe FOXD1-AS1 function in vitro and in vivo. Dual luciferase reporter gene analysis, Western blot, and ChIRP-MS were used to detect microRNAs and protein that combine with FOXD1-AS1. Results FOXD1-AS1 was upregulated and directly correlated with the glioma grade, and it was localized in both the nucleus and the cytoplasm of the glioma cell. FOXD1-AS1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration, and apoptosis, while FOXD1-AS1 overexpression resulted in opposite effects. Additionally, in vivo experiments showed that FOXD1-AS1 knockdown reduced tumor volume and weight. More importantly, mechanical studies revealed that FOXD1-AS1 targeted both miR339-5p and miR342-3p (miR339/342). Furthermore, protein eukaryotic translation initiation factor 5 subunit A (eIF5a) resulted a direct target of FOXD1-AS1. Conclusions These data indicated that FOXD1-AS1, a miR339/342 target, affected biological processes via protein eIF5a; thus, it might be considered as a new therapeutic target for glioblastoma.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.13152

LncRNA FOXD1-AS1 acts as a potential oncogenic biomarker in glioma.

Previous studies reported that the proline-rich transmembrane protein 2 (PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 mutation is a potential cause of febrile seizures, including febrile seizures plus (FS+), generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS); thus, it may provide a new drug target for personalized medicine for febrile seizure patients. We screened PRRT2 exons in a cohort of 136 epileptic patients with febrile seizures, including FS+, GEFS+ and DS. PRRT2 genetic mutations were identified in 25 out of 136 (18.4%) febrile seizures in epileptic patients. Five loss-of-function and coding missense mutations were identified: c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His) and c.623C>A (p.Ser208Tyr). PRRT2 variants were probably involved in the etiology of febrile seizures in epileptic patients.

https://www.mdpi.com/1422-0067/15/12/23408/pdf

PRRT2 mutations are related to febrile seizures in epileptic patients.

// Chen-Xue Mao 1, 3 , Ji-Ye Yin 1, 3 , Ying Zhang 1, 3 , Zhi-Bin Wang 1, 3 , Zhi-Quan Yang 2 , Zheng-Wen He 4 , Xiang-Min Li 5 , Xiao-Yuan Mao 1, 3 , Ru-Tao Cui 6 , Xue-Jun Li 2 , Xi Li 1, 3 , Wei Zhang 1, 3 , Hong-Hao Zhou 1, 3 and Zhao-Qian Liu 1, 3 1 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China 2 Department Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, P. R. China 3 Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China 4 Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410014, P. R. China 5 Department of Emergency, Xiangya Hospital, Central South University, Changsha 410008, P. R. China 6 Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA Correspondence to: Zhao-Qian Liu, email: liuzhaoqian63@126.com Keywords: astrocytoma, calcium signaling pathway, IDH, molecular classification, chemokine signaling pathway Received: July 29, 2017     Accepted: August 23, 2017     Published: October 25, 2017 ABSTRACT Aim: This study will explore the genetic and epigenetic alterations in astrocytomas, and identify the critical molecular signatures and signaling pathways for prognosis assessment by multiplatform comprehensive analysis. Method: We performed integration analyses of incorporating DNA methylation, mRNA expression, microRNA expression, and long non-coding RNA (lncRNA) expression in 33 astrocytic tumor tissues and 9 non-tumor brain tissues. Result: We observed that 11,795 DNA methylation sites, 3,627 genes, 136 microRNAs, and 3,334 lncRNAs were significantly differential between tumors and non-tumor brain tissues, and the filtered signatures through comprehensive analysis were significantly enriched in calcium signaling pathway. Furthermore, four signatures involved in calcium signaling pathway and age could contribute to predicting the patients’ overall survival. Additionally, we identified differentially expressed signatures between IDH-mutated and IDH wild-type astrocytic tumors, and complement and coagulation cascades pathway was the most significant pathway in functional enrichment analysis using multiplatform data. The IDH wild-type astrocytomas were divided into two subtypes by Cluster of Cluster (CoC) analysis, one of which was enriched for astrocytomas overexpressed in chemokine signaling pathway. Conclusion: The calcium signaling pathway played a key role in astrocytoma tumorigenesis and prognosis. IDH mutation was a vital biomarker, and resulted in the change of expression level in complement and coagulation cascades pathway. The chemokine signaling pathway could characterize subtypes of IDH wild-type astrocytomas.

/pdf/the-molecular-classification-of-astrocytic-tumors-4tqr7yhf8r.pdf

The molecular classification of astrocytic tumors.

Abstract Background Seizures are a common symptom in glioma patients, and they can cause brain dysfunction. However, the mechanism by which glioma-related epilepsy (GRE) causes alterations in brain networks remains elusive. Objective To investigate the potential pathogenic mechanism of GRE by analyzing the dynamic expression profiles of microRNA/ mRNA/ lncRNA in brain tissues of glioma patients. Methods Brain tissues of 16 patients with GRE and 9 patients with glioma without epilepsy (GNE) were collected. The total RNA was dephosphorylated, labeled, and hybridized to the Agilent Human miRNA Microarray, Release 19.0, 8 × 60 K. The cDNA was labeled and hybridized to the Agilent LncRNA + mRNA Human Gene Expression Microarray V3.0, 4 × 180 K. The raw data was extracted from hybridized images using Agilent Feature Extraction, and quantile normalization was performed using the Agilent GeneSpring. P-value &lt; 0.05 and absolute fold change &gt; 2 were considered the threshold of differential expression data. Data analyses were performed using R and Bioconductor. Results We found that 3 differentially expressed miRNAs (miR-10a-5p, miR-10b-5p, miR-629-3p), 6 differentially expressed lncRNAs (TTN-AS1, LINC00641, SNHG14, LINC00894, SNHG1, OIP5-AS1), and 49 differentially expressed mRNAs play a vitally critical role in developing GRE. The expression of GABARAPL1, GRAMD1B, and IQSEC3 were validated more than twofold higher in the GRE group than in the GNE group in the validation cohort. Pathways including ECM receptor interaction and long-term potentiation (LTP) may contribute to the disease’s progression. Meanwhile, We built a lncRNA-microRNA-Gene regulatory network with structural and functional significance. Conclusion These findings can offer a fresh perspective on GRE-induced brain network changes. 

/pdf/integrative-analysis-of-expression-profile-indicates-the-ecm-153754ug.pdf

Integrative analysis of expression profile indicates the ECM receptor and LTP dysfunction in the glioma-related epilepsy

/pdf/integrative-analysis-of-expression-profile-indicates-the-ecm-1zyr0uok.pdf

Zheng-Wen He

Papers

LncRNA FOXD1-AS1 acts as a potential oncogenic biomarker in glioma.

PRRT2 mutations are related to febrile seizures in epileptic patients.

The molecular classification of astrocytic tumors.

Integrative analysis of expression profile indicates the ECM receptor and LTP dysfunction in the glioma-related epilepsy

Integrative analysis of expression profile indicates the ECM receptor and LTP dysfunction in the glioma-related epilepsy