Evidence map›Paper›PMID 38079020›Full record

ArticleActa neuropathologica2023

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Sara Hadad, Rohit Gupta, Nancy Ann Oberheim Bush, Jennie W Taylor, Javier E Villanueva-Meyer, Jacob S Young, Jasper Wu, Ajay Ravindranathan, Yalan Zhang, Gayathri Warrier and 20 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed, 1 pooled it
8.1field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

35 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. "Updates on diagnostic and prognostic molecular biomarkers of CNS tumors".Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026
    Review
  4. Review
  5. Article
  6. Review
  7. A Genomically Tailored Multiagent Precision Medicine Clinical Trial for Adults with Recurrent Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
    Article
  8. Review
  9. Article
  10. Article
  11. Review
  12. Article
  13. Article
  14. Article
  15. Article
  16. Review
  17. Article
  18. DNA Methylation-Based Classification of Kidney Neoplasms.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2025
    Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

30 authors at 1 institution in 1 country.

Sara Hadad *Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Rohit Gupta *Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Nancy Ann Oberheim BushDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Jennie W TaylorDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Javier E Villanueva-MeyerDepartment of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
Jacob S YoungDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Jasper WuDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Ajay RavindranathanDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Yalan ZhangDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Gayathri WarrierDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Lucie McCoyDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Anny ShaiDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Melike PekmezciDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Arie PerryDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Andrew W BollenDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Joanna J PhillipsDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Steve E BraunsteinDepartment of Radiation Oncology, University of California, San Francisco, CA, USA.
David R RaleighDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Philip TheodosopoulosDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Manish K AghiDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Edward F ChangDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Shawn L Hervey-JumperDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Joseph F CostelloDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
John de GrootDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Nicholas A ButowskiDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Jennifer L ClarkeDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Susan M ChangDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Mitchel S BergerDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Annette M MolinaroDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. annette.molinaro@ucsf.edu.
David A SolomonDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA. david.solomon@ucsf.edu.ORCID 0000-0003-4571-7999
University of California, San Francisco · US

Funding

Tissue CoreP50CA097257 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Joseph F Costello · 2002 to 2026
$57.4M
Training Program in Translational Brain Tumor ResearchT32CA151022 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Joseph F Costello · 2010 to 2026
$6.6M
Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systemsR01CA227136 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AGHI, MANISH · 2018 to 2022
$2.2M
Retroviral RLI immunomodulatory gene therapy for glioblastomaR01NS123808 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Manish Aghi · 2022 to 2026
$2.1M
NCI NIH HHS P50 CA097257NCI NIH HHS R01 CA227136NCI NIH HHS T32 CA151022NINDS NIH HHS R01 NS123808
6 · The paper itself

Abstract

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Indexed as

Brain NeoplasmsGlioblastomaAdultAgedChildHomozygoteHumansImmune Checkpoint InhibitorsIsocitrate DehydrogenaseMiddle AgedMutationProspective StudiesSequence DeletionImmune Checkpoint InhibitorsIsocitrate DehydrogenaseGiant cell glioblastomaHypermutationImmune checkpoint blockadeImmunotherapyLynch syndromeMismatch repair deficiencyMolecular neuro-oncologyMolecular neuropathologyPOLEUltrahypermutation

Identifiers

PMID38079020
PMCPMC10713691
OpenAlexW4389547988

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.