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Updated: Jun 7, 2025
Digital Spatial Profiling for Characterization of the Microenvironment in Adult-Type Diffusely Infiltrating Glioma
Published on: September 13, 2022
Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular
Calixto-Hope G Lucas1,2,3, Nadeem N Al-Adli1,4, Jacob S Young1,4
1UCSF Brain Tumor Center, University of California, San Francisco, California, USA.
Background:
Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.
Methods:
Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.
Results:
While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.
Conclusions:
Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.
Insights
Glioblastoma evolves uniquely in each patient, impacting treatment response. Understanding this genetic and epigenetic evolution is key to improving survival for this aggressive brain cancer.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Epigenetics
Background:
- IDH-wildtype glioblastoma has poor prognosis despite advances.
- Molecular basis for varied treatment response to standard care is unknown.
Purpose of the Study:
- Investigate molecular evolution in glioblastoma.
- Identify factors influencing differential treatment responses.
Main Methods:
- Histopathologic, genomic, and epigenomic analysis of 106 patient glioblastoma samples.
- Paired analysis of initial and recurrent tumors.
Main Results:
- Early genetic events (TERT, CDKN2A) were shared; later events (EGFR, PTEN, NF1) were tumor-specific.
- Glioblastomas showed diverse epigenomic changes (hypermethylation, hypomethylation, stable).
- Sarcomatous transformation linked to specific alterations (NF1, TP53, RB1) and mesenchymal epigenetics.
- Temozolomide-induced hypermutation correlated with longer survival and was associated with MGMT promoter methylation.
- An epigenomic evolution signature predicted clinical outcomes.
Conclusions:
- Glioblastoma exhibits diverse genetic, epigenetic, and cellular evolution.
- This evolution impacts patient prognosis and treatment response.
