CCNB2 is a novel prognostic factor and a potential therapeutic target in Low-grade glioma (LGG)

Abstract:Background: Cyclin B2 (CCNB2) is an important component of the cyclin pathway and plays a key role in the occurrence and development of cancer. However, the correlation between prognosis of low-grade glioma (LGG), CCNB2, and tumor infiltrating lymphocytes is not clear. Methods: The expression of CCNB2 in LGG was queried in Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and TIMER databases. The relationships between CCNB2 and the clinicopathological features of LGG were analyzed using the Chinese Glioma Genome Atlas (CGGA) database. The relationship between CCNB2 expression and overall survival (OS) was evaluated by GEPIA2. The correlation between CCNB2 and LGG immune infiltration was analyzed by the TIMER database. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect CCNB2 expression. Results: The expression of CCNB2 differed across different tumor tissues, but was higher in LGG than in normal tissues. LGG patients with high expression of CCNB2 have poorer prognosis. The expression of CCNB2 was correlated with age, WHO grade, IDH mutational status, 1p/19q codeletion status, and other clinicopathological features. The expression of CCNB2 in LGG was positively correlated with the infiltration level of B cells, dendritic cells, and macrophages. qRT-PCR results revealed that the expression of CCNB2 in LGG tissues was higher than normal tissues and higher expression of CCNB2 was associated with worse prognosis. Conclusion: CCNB2 may be used as a potential biomarker to determine the prognosis of LGG and is also related to immune infiltration.

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Prognosis and immune function of Synaptotagmin-4 in gastric cancer and brain low-grade glioma

10.21203/rs.3.rs-21652/v1 ◽

2020 ◽

Author(s):

Siyuan Jiang ◽

Lizhe Zhu ◽

Chao Jiang ◽

Shibo Yu ◽

Bin Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Immune Function ◽

Treg Cells ◽

Low Grade Glioma ◽

Low Grade ◽

Lower Grade ◽

Expression Levels ◽

Immune Infiltration ◽

Normal Tissues ◽

Kaplan Meier

Abstract Background Synaptotagmins (SYTs) are a family of proteins whose primary feature is the calcium sensor in vesicle transport and exocytosis. SYT4 is one of them, but the relationship between SYT4 and cancer remains unclear. We aim to explore the prognosis and immune function of SYT4 in gastric cancer and low-grade glioma. Methods These databases were used to study the immunological and prognostic role of SYT4 in cancers, including the Oncomine database, Kaplan-Meier plotter, GEPIA2, TIMER, and CGGA. Results The study suggested that the expression levels of SYT4 were lower in both gastric cancer and glioma, compared to the normal tissues. And SYT4 played a protective and harmful role in low-grade gliomas and gastric cancer, respectively. Moreover, we found that a difference between SYT4 expression and the levels of immune infiltration in stomach adenocarcinoma (STAD) and brain lower-grade glioma (LGG). Besides, after exploring the association between the expression levels of SYT4 and markers of immune cells in these two cancers, we found that markers of monocytes, M1/ M2, tumor-associated macrophages (TAMs), Treg cells and SYT4 expressions had an opposite correlation in STAD and LGG. Conclusions SYT4 had an effect on the prognosis of gastric cancer and glioma patients and was related to immune infiltration by regulating TAMs and Treg cells. SYT4 can be used as a prognostic biomarker for STAD and LGG.

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Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low-grade glioma

BMC Cancer ◽

10.1186/s12885-021-08456-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiajie Lu ◽

Yuecheng Peng ◽

Rihong Huang ◽

Zejia Feng ◽

Yongyang Fan ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Low Grade Glioma ◽

Gene Set Enrichment Analysis ◽

Low Grade ◽

Ppi Network ◽

Myeloid Dendritic Cells ◽

Immune Infiltration ◽

Normal Tissues ◽

Worse Prognosis

Abstract Background Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). Methods The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

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Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low‑grade glioma

10.21203/rs.3.rs-376032/v1 ◽

2021 ◽

Author(s):

Jiajie Lu ◽

Yuecheng Peng ◽

Rihong Huang ◽

Zejia Feng ◽

Yongyang Fan ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Low Grade Glioma ◽

Gene Set Enrichment Analysis ◽

Low Grade ◽

Ppi Network ◽

Myeloid Dendritic Cells ◽

Immune Infiltration ◽

Normal Tissues ◽

Worse Prognosis

Abstract Background: Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low‑grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low‑grade glioma (LGG).Methods: The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results: Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion: TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

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Glioma with Leptomeningeal Spread Mimics Chronic Meningoencephalitis in a Young Adult

Case Reports in Neurology ◽

10.1159/000513562 ◽

2021 ◽

pp. 179-183

Author(s):

Ann-Kristin Becker ◽

Marta Leonora Frank ◽

Michael Friese ◽

Joachim Röther

Keyword(s):

Brain Tumor ◽

Back Pain ◽

Young Adult ◽

Lower Back Pain ◽

Low Grade Glioma ◽

Low Grade ◽

Who Grade ◽

Leptomeningeal Spread ◽

Lower Back ◽

Uncommon Case

The most malignant type of intrinsic brain tumor is glioblastoma (WHO grade IV). Primary leptomeningeal spread is rare and leads to a variety of differential considerations, as there is no typical clinical or imaging pattern. Here we present a rare and uncommon case of a primary leptomeningeal glioblastoma in combination with a low-grade glioma in a 21-year-old male, initially presenting with only headache and lower back pain. The presented case illustrates the challenging differential considerations and the severe course of leptomeningeal glioblastomas.

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Surgery for low-grade glioma infiltrating the central cerebral region: location as a predictive factor for neurological deficit, epileptological outcome, and quality of life

Journal of Neurosurgery ◽

10.3171/2013.5.jns122235 ◽

2013 ◽

Vol 119 (2) ◽

pp. 318-323 ◽

Cited By ~ 37

Author(s):

Philippe Schucht ◽

Fadi Ghareeb ◽

Hugues Duffau

Keyword(s):

Quality Of Life ◽

Return To Work ◽

Seizure Control ◽

Extent Of Resection ◽

Low Grade Glioma ◽

Neurological Deficits ◽

Main Concern ◽

Low Grade ◽

Who Grade

Object A main concern with regard to surgery for low-grade glioma (LGG, WHO Grade II) is maintenance of the patient's functional integrity. This concern is particularly relevant for gliomas in the central region, where damage can have grave repercussions. The authors evaluated postsurgical outcomes with regard to neurological deficits, seizures, and quality of life. Methods Outcomes were compared for 33 patients with central LGG (central cohort) and a control cohort of 31 patients with frontal LGG (frontal cohort), all of whom had had medically intractable seizures before undergoing surgery with mapping while awake. All surgeries were performed in the period from February 2007 through April 2010 at the same institution. Results For the central cohort, the median extent of resection was 92% (range 80%–97%), and for the frontal cohort, the median extent of resection was 93% (range 83%–98%; p = 1.0). Although the rate of mild neurological deficits was similar for both groups, seizure freedom (Engel Class I) was achieved for only 4 (12.1%) of 33 patients in the central cohort compared with 26 (83.9%) of 31 patients in the frontal cohort (p < 0.0001). The rate of return to work was lower for patients in the central cohort (4 [12.1%] of 33) than for the patients in the frontal cohort (28 [90.3%] of 31; p < 0.0001). Conclusions Resection of central LGG is feasible and safe when appropriate intraoperative mapping is used. However, seizure control for these patients remains poor, a finding that contrasts markedly with seizure control for patients in the frontal cohort and with that reported in the literature. For patients with central LGG, poor seizure control ultimately determines quality of life because most will not be able to return to work.

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Induction of Robust Type-I CD8+ T-cell Responses in WHO Grade 2 Low-Grade Glioma Patients Receiving Peptide-Based Vaccines in Combination with Poly-ICLC

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-14-1790 ◽

2014 ◽

Vol 21 (2) ◽

pp. 286-294 ◽

Cited By ~ 58

Author(s):

Hideho Okada ◽

Lisa H. Butterfield ◽

Ronald L. Hamilton ◽

Aki Hoji ◽

Masashi Sakaki ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Low Grade Glioma ◽

Low Grade ◽

Type I ◽

Who Grade ◽

Cell Responses

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LGG-12. SAFETY AND EFFICACY OF DUAL THERAPY WITH DABRAFENIB AND TRAMETINIB IN AN INFANT WITH BRAF V600E MUTANT INOPERABLE LOW GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab090.136 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i34-i34

Author(s):

Sage Green ◽

Andrew Walter ◽

Joseph Piatt ◽

Gurcharanjeet Kaur

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Cauda Equina ◽

Dual Therapy ◽

Low Grade Glioma ◽

Braf V600e ◽

Global Developmental Delay ◽

Low Grade ◽

Who Grade ◽

Safety And Efficacy

Abstract Objective To describe safety and efficacy of dual targeted therapy with dabrafenib (BRAFi) and trametinib (MEKi) in an infant with inoperable low grade glioma with BRAF V600E mutation. Introduction Safety and efficacy of dual targeted therapy with BRAFi and MEKi for pediatric low grade glioma (pLGG) is currently being evaluated, however, infants are usually not included in these clinical trials. Case We report a case of a 2-month-old male infant who presented with involuntary movements and gaze deviation concerning for seizures. MRI brain revealed a tumor involving the medulla, T2/FLAIR dimensions: 2.5 x 2.2 x 2.7 cm and drop metastases to the cauda equina. An EEG ruled out seizure activity. Tumor biopsy was performed revealing Ganglioglioma, WHO grade I. IHC and somatic next generation sequencing revealed BRAF V600E point mutation. Germline testing was negative. Due to tumor progression on traditional chemotherapy, compassionate use of dual targeted therapy with dabrafenib (5.25mg/kg/day divided twice daily) and trametinib (0.032mg/kg daily) was initiated at 4.5 months of age. The patient has tolerated dual therapy for nearly 1 year without significant toxicity with exception of grade I skin rash. In terms of functional outcomes, previously noticed vocal cord paresis has resolved and our patient with global developmental delay continues to make developmental gains, albeit slowly. On recent neuroimaging, pLGG has continued to grow T2/FLAIR dimensions: 3.5 x 3.5 x 3.7 cm, however, combination therapy has halted the rate of growth of this tumor. Conclusion To our knowledge, our patient is the youngest to receive combination of BRAFi and MEKi. Tumor targeted therapy could be an important treatment option for infants with inoperable pLGG where aggressive surgery and radiation therapy are associated with significant morbidity. Multi-institutional clinical trials that include infants are needed to further comment on safety and efficacy of these agents.

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Contemporary assessment of extent of resection in molecularly defined categories of diffuse low-grade glioma: a volumetric analysis

Journal of Neurosurgery ◽

10.3171/2019.6.jns19972 ◽

2020 ◽

Vol 133 (5) ◽

pp. 1291-1301 ◽

Cited By ~ 5

Author(s):

Vasileios K. Kavouridis ◽

Alessandro Boaro ◽

Jeffrey Dorr ◽

Elise Y. Cho ◽

J. Bryan Iorgulescu ◽

...

Keyword(s):

Tumor Volume ◽

Cox Regression ◽

Molecular Subtypes ◽

Progression Free Survival ◽

Residual Tumor ◽

Extent Of Resection ◽

Low Grade Glioma ◽

Low Grade ◽

Who Grade ◽

Free Survival

OBJECTIVEWhile the effect of increased extent of resection (EOR) on survival in diffuse infiltrating low-grade glioma (LGG) patients is well established, there is still uncertainty about the influence of the new WHO molecular subtypes. The authors designed a retrospective analysis to assess the interplay between EOR and molecular classes.METHODSThe authors retrospectively reviewed the records of 326 patients treated surgically for hemispheric WHO grade II LGG at Brigham and Women’s Hospital and Massachusetts General Hospital (2000–2017). EOR was calculated volumetrically and Cox proportional hazards models were built to assess for predictive factors of overall survival (OS), progression-free survival (PFS), and malignant progression–free survival (MPFS).RESULTSThere were 43 deaths (13.2%; median follow-up 5.4 years) among 326 LGG patients. Median preoperative tumor volume was 31.2 cm3 (IQR 12.9–66.0), and median postoperative residual tumor volume was 5.8 cm3 (IQR 1.1–20.5). On multivariable Cox regression, increasing postoperative volume was associated with worse OS (HR 1.02 per cm3; 95% CI 1.00–1.03; p = 0.016), PFS (HR 1.01 per cm3; 95% CI 1.00–1.02; p = 0.001), and MPFS (HR 1.01 per cm3; 95% CI 1.00–1.02; p = 0.035). This result was more pronounced in the worse prognosis subtypes of IDH-mutant and IDH-wildtype astrocytoma, for which differences in survival manifested in cases with residual tumor volume of only 1 cm3. In oligodendroglioma patients, postoperative residuals impacted survival when exceeding 8 cm3. Other significant predictors of OS were age at diagnosis, IDH-mutant and IDH-wildtype astrocytoma classes, adjuvant radiotherapy, and increasing preoperative volume.CONCLUSIONSThe results corroborate the role of EOR in survival and malignant transformation across all molecular subtypes of diffuse LGG. IDH-mutant and IDH-wildtype astrocytomas are affected even by minimal postoperative residuals and patients could potentially benefit from a more aggressive surgical approach.

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