Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy

Vasudevaraja, Varshini; Rodriguez, Javier Hernaez; Pelorosso, Cristiana; Zhu, Kaicen; Buccoliero, Anna Maria; Onozato, Maristela L.; Mohamed, Hussein; Serrano, Jonathan; Tredwin, Lily; Garonzi, Marianna; Forcato, Claudio; Zeck, Briana; Ramaswami, Sitharam; Stafford, James M.; Faustin, Arline; Friedman, Daniel; Hidalgo, Eveline Teresa; Zagzag, David; Skok, Jane A.; Heguy, Adriana; Chiriboga, Luis; Conti, Valerio; Guerrini, Renzo; Iafrate, A. John; Devinsky, Orrin; Tsirigos, Aristotelis; Golfinos, John G.; Snuderl, Matija

doi:10.1093/jnen/nlaa137

Cited by 8 publications

(5 citation statements)

References 32 publications

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“…Interestingly, Anwar et al identified frequent recurrence of CNVs in PDGFRA gene in a next-generation sequencing-based CNV study of invasive breast cancer patients (Anwar et al 2020 ). PDGFRA CN gain was also detected in intractable epilepsy and high-grade astrocytoma and found to be significantly associated with the treatment and prognosis of the disease (Phillips et al 2013 ; Vasudevaraja et al 2021 ). While the importance of the tumor microenvironment has been increasingly recognized, the complexity of interaction between tumor cells and their microenvironment is becoming evident.…”

Section: Introductionmentioning

confidence: 99%

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Liu

Shan

et al. 2022

Mol Genet Genomics

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We investigated the copy number variation (CNV) of PDGFRA pathway across all common cancer types as well as its clinical relevance. This study included a total of 10,678 patients with pan-cancerous species involving 33 types of cancers and patient information was obtained from The Cancer Genome Atlas. According to the PDGFRA pathway CNV, all samples were divided into copy number gain (CN gain) group and No CN gain group. The analysis of loss of heterozygosity (LOH) fraction, CNV burden, tumor mutation burden (TMB), and the number of immunogenic mutations were performed, as well as the correlation analysis of PDGFRA pathway CN gain with tumor-related signaling pathways and tumor-infiltrating immune cell subpopulations. The results showed that CN gain of PDGFRA pathway in the cancer patients was associated with significantly shorter overall survival. The CN gain of PDGFRA pathway was identified as a prognostic risk factor for some tumors. CN gain was accompanied by an altered percentage of LOH, CNV burden, TMB, the number of immunogenic mutations were increased and tumor-infiltrating immune cell subpopulations were less. While certain tumor-related signaling pathways, such as hypoxia, cell cycle, DNA repair, and epithelial-mesenchymal transition were more enriched in the CN gain group, quiescence, and inflammation pathways were more enriched in the No CN gain group. In conclusion, PDGFRA pathway CNV gain may be a poor prognostic factor in cancer patients.

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Section: Introductionmentioning

confidence: 99%

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Liu

Shan

et al. 2022

Mol Genet Genomics

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“…This evidence illustrates that mast cell involvement in the immune response to achieve neuroinflammatory regulation has a potential regulatory role in epilepsy. Further, It was reported that EGFR was significantly associated with the risk of epilepsy occurrence ( 48 ), and overexpression of EGFR caused by focal copy number gains was identified in epilepsy ( 49 ). EGFR belongs to the receptor tyrosine kinase family.…”

Section: Discussionmentioning

confidence: 99%

Identification of epidermal growth factor receptor as an immune-related biomarker in epilepsy using multi-transcriptome data

Luo¹,

Han²,

Chen³

et al. 2023

Transl Pediatr

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Background Epilepsy is a chronic disease that is characterized by transient brain dysfunction caused by an abrupt abnormal neuronal discharge. Recent studies have indicated that the pathways related to inflammation and innate immunity play significant roles in the pathogenesis of epilepsy, suggesting an interrelationship between immunity and inflammatory processes and epilepsy. However, the immune-related mechanisms are still not precisely understood; therefore, this study aimed to explore the immune-related mechanisms in epilepsy disorders, highlight the role of immune cells at the molecular level in epilepsy, and provide therapeutic targets for patients with epilepsy. Methods Brain tissue samples from healthy and epileptic individuals were collected for transcriptome sequencing to identify differentially expressed genes (DEGs) and differentially expressed (DE)-long coding RNAs (lncRNAs). Based on interactions from the miRcode, starBase2.0, miRDB, miRTarBase, TargetScan, and ENCORI databases, a lncRNA-associated competitive endogenous RNA (ceRNA) network was created. Gene ontology and the Kyoto encyclopedia of genes analyses established that the genes in the ceRNA network were mainly enriched in immune-related pathways. Immune cell infiltration, screening, and protein-protein interaction analyses of the immune-related ceRNAs, and correlation analysis between immune-related core messenger RNA (mRNA) and immune cells were also performed. Results Nine hub genes ( EGFR, GRB2, KRAS, FOS, ESR1, MAPK1, MAPK14, MAPK8, and PPARG ) were obtained. Also, 38 lncRNAs, one miRNA ( hsa-miR-27a-3p ), and one mRNA ( EGFR ) comprised the final core ceRNA network. Mast cells, plasmacytoid dendritic cells, and immature dendritic cells all showed positive correlations with EGFR, while Cluster of differentiation 56 dim natural killer cells (CD56dim natural killer cells) showed negative correlations. Finally, we employed an epilepsy mouse model to validate EGFR , which is consistent with disease progression. Conclusions In conclusion, the pathophysiology of epilepsy was correlated with EGFR . Thus, EGFR could be a novel biomarker of juvenile focal epilepsies, and our findings provide promising therapeutic targets for epilepsy.

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“…PMG is a group of highly heterogeneous and difficult to classify MCD (55, 56). Their description is primarily based on their localization (by MRI; e.g., focal, multifocal, or generalized, unilateral or bilateral symmetric/asymmetric) and correlation with clinical aspects including developmental course, growth anomalies, and dysmorphism, seizure history, family history, and genetic testing of blood for PMG‐associated genes (24). Over 40 genes with germline mutations have so far been linked to PMG types and syndromes, but only very recently also brain somatic events were reported.…”

Section: Brain Somatic 1q Trisomymentioning

confidence: 99%

Molecular diagnostics in drug‐resistant focal epilepsy define new disease entities

et al. 2021

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Structural brain lesions, including the broad range of malformations of cortical development (MCD) and glioneuronal tumors, are among the most common causes of drug‐resistant focal epilepsy. Epilepsy surgery can provide a curative treatment option in respective patients. The currently available pre‐surgical multi‐modal diagnostic armamentarium includes high‐ and ultra‐high resolution magnetic resonance imaging (MRI) and intracerebral EEG to identify a focal structural brain lesion as epilepsy underlying etiology. However, specificity and accuracy in diagnosing the type of lesion have proven to be limited. Moreover, the diagnostic process does not stop with the decision for surgery. The neuropathological diagnosis remains the gold standard for disease classification and patient stratification, but is particularly complex with high inter‐observer variability. Here, the identification of lesion‐specific mosaic variants together with epigenetic profiling of lesional brain tissue became new tools to more reliably identify disease entities. In this review, we will discuss how the paradigm shifts from histopathology toward an integrated diagnostic approach in cancer and the more recent development of the DNA methylation‐based brain tumor classifier have started to influence epilepsy diagnostics. Some examples will be highlighted showing how the diagnosis and our mechanistic understanding of difficult to classify structural brain lesions associated with focal epilepsy has improved with molecular genetic data being considered in decision making.

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Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy

Cited by 8 publications

References 32 publications

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Identification of epidermal growth factor receptor as an immune-related biomarker in epilepsy using multi-transcriptome data

Molecular diagnostics in drug‐resistant focal epilepsy define new disease entities

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