Neuro-oncologyNov 19, 2024

Molecular and cellular changes over time in aggressive brain tumors linked to different treatment outcomes

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 29, 2026

Abstract

A comprehensive evaluation of 106 glioblastoma patients reveals significant genetic and epigenetic heterogeneity associated with treatment responses.

TERT promoter mutation and CDKN2A homozygous deletion were common early events in both initial and recurrent tumors.
Most recurrent genetic alterations, including EGFR, PTEN, and NF1, were specific to either initial or recurrent tumors, suggesting late acquisition during tumor evolution.
Glioblastomas displayed diverse patterns of epigenomic evolution, with subsets showing increased hypermethylation, hypomethylation, or stability.
Tumors that transformed into a sarcomatous phenotype recurred more quickly and were associated with alterations in NF1, TP53, and RB1.
Patients who developed after temozolomide treatment experienced longer intervals to recurrence and improved overall survival.
Increased methylation at four specific CpG sites in the MGMT promoter correlated with the development of somatic hypermutation.

Simplified

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 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 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.

Key numbers

27.8 months

Interval to Recurrence Increase

Interval to recurrence for patients with post-temozolomide treatment.

67.9 months

Overall Survival Increase

Overall survival for patients with compared to those without.

9.0 months

Interval to Recurrence Decrease

Interval to recurrence for patients who developed sarcomatous transformation.

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Funding

Competing interests

Jennie Taylor, John de Groot, Annette Molinaro, Joseph Costello, Aaron Diaz, Susan Chang, and Mitchel Berger are members of the editorial board of Neuro-Oncology but were not involved in the handling or decision making for this manuscript. Jennie Taylor receives grant support from Bristol Myers Squibb and Servier Pharmaceuticals and serves on the advisory board for Servier Pharmaceuticals. The remaining authors declare that they have no competing interests related to this study.

PubMed

Molecular and cellular changes over time in aggressive brain tumors linked to different treatment outcomes

Abstract

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