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Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses.

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Author information

Affiliations

  • 1. UCSF Brain Tumor Center, University of California, San Francisco, California, USA.
      Authors
    • Lucas CG 1
    • Al-Adli NN 1
    • Young JS 1
    • Gupta R 1
    • Morshed RA 1
    • Wu J 1
    • Ravindranathan A 1
    • Shai A 1
    • Oberheim Bush NA 1
    • Taylor JW 1
    • de Groot J 1
    • Villanueva-Meyer JE 1
    • Pekmezci M 1
    • Perry A 1
    • Bollen AW 1
    • Theodosopoulos PV 1
    • Aghi MK 1
    • Chang EF 1
    • Hervey-Jumper SL 1
    • Raleigh DR 1
    • Molinaro AM 1
    • Costello JF 1
    • Diaz AA 1
    • Clarke JL 1
    • Butowski NA 1
    • Phillips JJ 1
    • Chang SM 1
    • Berger MS 1
    • Solomon DA 1
    (29 authors)

ORCIDs linked to this article

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Neuro-oncology, 19 Nov 2024, :noae214
https://doi.org/10.1093/neuonc/noae214 PMID: 39560080 

Abstract 

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.

Full text links 

Read article at publisher's site: https://doi.org/10.1093/neuonc/noae214

Funding 

Funders who supported this work.

Gilbert Family Foundation

    NCI NIH HHS (1)

    NIH HHS (1)

    Panattoni Family Foundation

      Sandler Foundation