IL-1 IDHWT GLIOBLASTOMA LONGITUDINAL MOLECULAR EVOLUTION

Abstract We performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses. While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (e.g., EGFR, PTEN, NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Further, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation at recurrence had inferior survival 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 hypermethylation at four 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. This talk will describe how GBM undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

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Publication Details

Journal
Neuro-Oncology Advances
Published
2024-11-29
DOI
https://doi.org/10.1093/noajnl/vdae173.107
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
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article

IL-1 IDHWT GLIOBLASTOMA LONGITUDINAL MOLECULAR EVOLUTION

Calixto‐Hope G. Lucas, Jacob S. Young, Mitchel Stuart Berger, David Ronan Raleigh et al.
Neuro-Oncology Advances
Glioma Diagnosis and Treatment
article

IL-1 IDHWT GLIOBLASTOMA LONGITUDINAL MOLECULAR EVOLUTION

Calixto‐Hope G. Lucas, Jacob S. Young, Mitchel Stuart Berger, David Ronan Raleigh, John Clarke, Jinsong Wu, Nadeem Al-Adli, Ramin A. Morshed, Annette M. Molinaro, Shawn L. Hervey‐Jumper, Philip V. Theodosopoulos, Manish K. Aghi, Javier Villanueva‐Meyer, Arie Perry, John de Groot, Melike Pekmezci, Raghav Gupta, Alyssa L. Bolen, Anny Shai, Jennie Taylor, David A. Solomon, J Costello, Nicholas Butowski, Nancy Ann Oberheim Bush, Aaron A. Diaz, Edward Yi Chang, Jeffrey J. Phillips, Susan M. Chang, A Ravindranthan
article en

Abstract

Abstract We performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses. While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (e.g., EGFR, PTEN, NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Further, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation at recurrence had inferior survival 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 hypermethylation at four 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. This talk will describe how GBM undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

Neuro-Oncology AdvancesVol. 6(Supplement_4)
Neurological Surgery (US)
Good health and well-being
Openalex Percentile: Top 61%
Glioma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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