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

Calixto-Hope G Lucas; Nadeem N Al-Adli; Jacob S Young; Rohit Gupta; Ramin A Morshed; Jasper Wu; Ajay Ravindranathan; Anny Shai; Nancy Ann Oberheim Bush; Jennie W Taylor; John de Groot; Javier E Villanueva-Meyer; Melike Pekmezci; Arie Perry; Andrew W Bollen; Philip V Theodosopoulos; Manish K Aghi; Edward F Chang; Shawn L Hervey-Jumper; David R Raleigh; Annette M Molinaro; Joseph F Costello; Aaron A Diaz; Jennifer L Clarke; Nicholas A Butowski; Joanna J Phillips; Susan M Chang; Mitchel S Berger; David A Solomon

doi:10.1093/neuonc/noae214

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

Neuro Oncol. 2024 Nov 19:noae214. doi: 10.1093/neuonc/noae214. Online ahead of print.

Authors

Calixto-Hope G Lucas^{1

2

3}, Nadeem N Al-Adli^{1

4}, Jacob S Young^{1

4}, Rohit Gupta^{1

2}, Ramin A Morshed^{1

4}, Jasper Wu^{1

2}, Ajay Ravindranathan^{1

2}, Anny Shai^{1

4}, Nancy Ann Oberheim Bush^{1

5

6}, Jennie W Taylor^{1

5

6}, John de Groot^{1

5

6}, Javier E Villanueva-Meyer^{1

7}, Melike Pekmezci^{1

2}, Arie Perry^{1

2

4}, Andrew W Bollen^{1

2}, Philip V Theodosopoulos^{1

4}, Manish K Aghi^{1

4}, Edward F Chang^{1

4}, Shawn L Hervey-Jumper^{1

4}, David R Raleigh^{1

2

4

8}, Annette M Molinaro^{1

4}, Joseph F Costello^{1

4}, Aaron A Diaz^{1

4}, Jennifer L Clarke^{1

5

6}, Nicholas A Butowski^{1

5}, Joanna J Phillips^{1

2

4}, Susan M Chang^{1

5}, Mitchel S Berger^{1

4}, David A Solomon^{1

2}

Affiliations

¹ UCSF Brain Tumor Center, University of California, San Francisco, California, USA.
² Department of Pathology, University of California, San Francisco, California, USA.
³ Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
⁴ Department of Neurological Surgery, University of California, San Francisco, California, USA.
⁵ Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, California, USA.
⁶ Department of Neurology, University of California, San Francisco, California, USA.
⁷ Department of Radiology & Biomedical Imaging, University of California, San Francisco, California, USA.
⁸ Department of Radiation Oncology, University of California, San Francisco, California, USA.

PMID: 39560080
DOI: 10.1093/neuonc/noae214

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.

Keywords: DNA methylation; glioblastoma; gliosarcoma; molecular neuropathology; temozolomide-induced hypermutation.

Abstract

Grants and funding