Practice of the New Integrated Molecular Diagnostics in Gliomas: Experiences and New Findings in a Single Chinese Center

Hu, Wanming; Wang, Fang; Xi, Shaoyan; Zhang, Xiao; Lai, Jun-Peng; Wu, Hui-Yu; Liu, Liling; Sai, Ke; Zeng, Jing

doi:10.7150/jca.38603

Cited by 13 publications

(22 citation statements)

References 57 publications

(52 reference statements)

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“…Methylation-specific PCR was conducted using an EZ DNA Methylation Kit (Zymo Research, Irvine, CA, USA) to determine the methylation status of the MGMT promoter, as described previously [ 5 ].…”

Section: Methodsmentioning

confidence: 99%

High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma, H3 G34-mutant: a glimmer of hope?

Duan

Zhong

et al. 2022

J Transl Med

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Background Diffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA). Methods Hematoxylin–eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data. Six G34-DHG patients from another organization were used as external validation. Results WES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months. Conclusions Our results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs.

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Section: Methodsmentioning

confidence: 99%

High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma, H3 G34-mutant: a glimmer of hope?

Duan

Zhong

et al. 2022

J Transl Med

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“…1p and 19q deletion status was detected using fluorescent in situ hybridization (FISH). The detailed protocol and assessment standard were described as a previous study ( 28 ).…”

Section: Methodsmentioning

confidence: 99%

CHI3L2 Is a Novel Prognostic Biomarker and Correlated With Immune Infiltrates in Gliomas

et al. 2021

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CHI3L2 (Chitinase-3-Like Protein 2) is a member of chitinase-like proteins (CLPs), which belong to the glycoside hydrolase 18 family. Its homologous gene, CHI3L1, has been extensively studied in various tumors and has been shown to be related to immune infiltration in breast cancer and glioblastoma. High CHI3L2 expression was reported to be associated with poor prognosis in breast cancer and renal cell carcinoma. However, the prognostic significance of CHI3L2 in glioma and its correlation between immune infiltration remains unclear. In this study, we examined 288 glioma samples by immunohistochemistry to find that CHI3L2 is expressed in tumor cells and macrophages in glioma tissues and highly expressed in glioblastoma and IDH wild-type gliomas. Relationships between CHI3L2 expression and clinical features (grade, age, Ki67 index, P53, PHH3 (mitotic figures), ATRX, TERTp, MGMTp, IDH, and 1p/19q co-deleted status) were evaluated. Kaplan-Meier survival was conducted to show high CHI3L2 expression in tumor cells (TC) and macrophage cells (MC) indicated poor prognosis in diffusely infiltrating glioma (DIG), lower-grade glioma (LGG), and IDH wild-type gliomas (IDH-wt). The overall survival time was higher in patients with dual-low CHI3L2 expression in TC and MC compared to those in patients with non-dual CHI3L2 expression and dual high expression in DIG and IDH wild-type gliomas. By univariate and multivariate analysis, we found that high CHI3L2 expression in tumor cells was an independent unfavorable prognostic factor in glioma patients. Moreover, we used two datasets (TCGA and CGGA) to verify the results of our study and explore the potential functional role of CHI3L2 by GO and KEGG analyses in gliomas. TIMER platform analysis indicated CHI3L2 expression was closely related to diverse marker genes of tumor immune infiltrating cells, including monocytes, TAMs, M1 macrophages, M2 macrophages, TGFβ1+ Treg and T cell exhaustion in GBM and LGG. Western Blot validated CHI3L2 is expressed in glioma cells and microglia cells. The results of flow cytometry showed that CHI3L2 induces the apoptosis of CD8+ T cells. In conclusion, these results demonstrate CHI3L2 is related to poor prognosis and immune infiltrates in gliomas, suggesting it may serve as a promising prognostic biomarker and represent a new target for glioma patients.

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“…Comprehensive literature review was performed, especially focusing on data in eastern countries. Approximately, the incidences of IDH1 mutation and MGMT promotor methylation are 15% and 40%, and the HRs of OS are 0.46 and 0.57, respectively [24][25][26][27][28][29][30]. We used these assumptions and incorporated status of IDH1 and MGMT promotor into multi-variate Cox regression model.…”

Section: Discussionmentioning

confidence: 99%

Use of Anti-Epileptic Drugs During Adjuvant Chemo-Radiotherapy is Associated with Increased Mortality in Patients with Glioblastoma: A Nationwide Population-Based Cohort Study

Lee¹,

Chao²,

Wei³

et al. 2020

Preprint

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BackgroundThere are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radiosensitizers to improve survival in glioblastoma (GBM) patients. We conducted a population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy (CCRT) on outcome.Methods1057 GBM patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant RT and temozolomide (TMZ), and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during CCRT (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for valproic acid (VPA), levetiracetam (LEV), and phenytoin were performed. Multivariate analyses were used to adjust for confounding factors. ResultsThere were 642 patients in the AED group while 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs. (22.6% vs 18%, p=0.078). Overall, the AED group had significantly increased risk of mortality (HR=1.18, p=0.016). In subgroup analyses, the significant detrimental effect was demonstrated in VPA (HR=1.29, p=0.0002), but not in LEV (HR=1.18, p=0.079) and phenytoin (HR = 0.98, p=0.862). When stratified by sex and age, this detrimental effect was seen in male and patients less than 65 years old in the VPA group.Conclusion:Survival was not improved and even worse in patients with AEDs during CCRT in this nationwide population-based study. Our real-world data did not support prophylactic use of AEDs for GBM.

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Practice of the New Integrated Molecular Diagnostics in Gliomas: Experiences and New Findings in a Single Chinese Center

Cited by 13 publications

References 57 publications

High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma, H3 G34-mutant: a glimmer of hope?

High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma, H3 G34-mutant: a glimmer of hope?

CHI3L2 Is a Novel Prognostic Biomarker and Correlated With Immune Infiltrates in Gliomas

Use of Anti-Epileptic Drugs During Adjuvant Chemo-Radiotherapy is Associated with Increased Mortality in Patients with Glioblastoma: A Nationwide Population-Based Cohort Study

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