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

Abstract

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.

Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors

“… 5 It has been found that alterations in the PDGFRA gene might indicate poor prognosis and potentially represent a therapeutic target for patients with G34-DHG. 14 One study exploring biomarkers of survival in 15 patients with G34-DHG demonstrated that patients exhibiting PDGFRA mutations tended to exhibit shorter OS, while those that had MUC16 alterations might have a more favorable survival, although patient numbers were limited and neither result was statistically significant. 14 Our study did not assess outcomes based on tumor mutational burden where hypermutation has been reported in some patients with G34-DHG at the time of relapse.…”

“… 14 One study exploring biomarkers of survival in 15 patients with G34-DHG demonstrated that patients exhibiting PDGFRA mutations tended to exhibit shorter OS, while those that had MUC16 alterations might have a more favorable survival, although patient numbers were limited and neither result was statistically significant. 14 Our study did not assess outcomes based on tumor mutational burden where hypermutation has been reported in some patients with G34-DHG at the time of relapse. 8 Tumor mutational burden might also be an important biomarker for future assessment on outcome and treatment.…”

“…Common co-alterations were selected based on availability and recognition in the literature including ATRX , TP53, PDGFRA , and MGMT promoter methylation. 1 , 7 , 14 When immunohistochemistry was used, cut-off percentages for ATRX and TP53 mutation status were set at 10% nuclear staining. 15 …”

Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?

“…Molecular investigations may be also useful to stratify the prognosis in a more precise manner. In fact, better prognosis is associated with the presence of MGMT promoter methylation and MUC gene mutations, while a worse prognosis is associated with PDGFRA mutations and the amplification of oncogenes, such as PDGFRA , EGFR , CDK4, and MDM2 ( Korshunov et al, 2016 ; Hu et al, 2022 ; Vuong et al, 2022 ). Furthermore, the demonstration of alterations in PDGFRA and MUC genes might be potentially useful to open up new therapeutic options for these patients ( Lucas et al, 2021 ; Hu et al, 2022 ).…”

H3G34-mutant diffuse hemispheric glioma with osseous metastases: a case report and literature review

“…It has been proposed via in vivo murine models that H3G34R/V mutations arise from GSX2+-expressing interneuron progenitor cells and that the mutations delay neuronal differentiation and increase PDGFRA overexpression, ultimately linking PDGFRA aberration to gliomagenesis [ 19 ]. While some studies indicate that the presence of mutations in PDGRA or EGFR may confer prognosis better than others [ 16 , 17 ], further investigation is required.…”