EGFR and TP53 mutations refine prognostic stratification of IDH-wildtype astrocytomas, not elsewhere classified.
9 affiliations
- 1Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, 890-8520, Japan. [email protected].
- 2Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, 890-8544, Japan.
- 3Center for Human Genome and Gene Analysis, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima City, 890-8544, Japan.
- 4Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, 890-8520, Japan.
- 5Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
- 6Department of Neurosurgery, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
- 7Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, 890-8544, Japan. [email protected].
- 8Center for Human Genome and Gene Analysis, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima City, 890-8544, Japan. [email protected].
- 9Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, 890-8520, Japan. [email protected].
Abstract
IDH-wildtype astrocytomas of histological grade 2 or 3 without the WHO 2021 molecular criteria for glioblastoma-TERT promoter mutation, EGFR amplification, or combined whole-chromosome 7 gain and 10 loss (+ 7/- 10)-are designated "Not Elsewhere Classified" (NEC), a residual category with clinical behavior ranging from indolent disease to courses clinically indistinguishable from glioblastoma (GBM). However, reliable molecular markers capable of resolving this heterogeneity have not been established. We retrospectively profiled a multi-institutional cohort comprising 38 adult IDH-wildtype astrocytoma NEC cases and 429 GBM controls using a bimodal DNA/RNA next-generation sequencing panel and, in 30 NEC cases, genome-wide DNA methylation profiling. NEC tumors were markedly heterogeneous: 21 of the 30 methylation profiles (70%) failed to match any reference class family, and the remaining nine were distributed across six categories, with Uniform Manifold Approximation and Projection (UMAP) showing scattered embedding adjacent to multiple high- and low-grade reference clusters, rather than a coherent NEC cluster. Against this heterogeneous background, two point mutations emerged as candidate markers for aggressive disease: EGFR mutations (3/38, 7.9%), all clustered in the extracellular domain, and TP53 mutations (8/38, 21.1%), predominantly in the DNA-binding domain. Both retained independent prognostic significance in Firth-penalized multivariate Cox regression (EGFR: HR 1.61, 95% CI 1.02-2.57, P = 0.028; TP53: HR 1.55, 95% CI 1.00-2.42, P = 0.041). NEC patients harboring EGFR and/or TP53 mutations showed an overall survival curve closely paralleling that of GBM (P = 0.9605) and significantly diverged from EGFR/TP53-wildtype NEC (P = 0.0011). Thus, despite the marked genomic and epigenomic heterogeneity within NEC, EGFR and TP53 point mutations may identify a high-risk NEC subgroup. This stratifier is deployable with routine targeted sequencing panels already widely used in diagnostic practice, and provides a practical refinement complementary to the cIMPACT-NOW Update 11 framework, pending prospective validation.
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BibTeX
@article{higa2026egfr,
title = {{EGFR and TP53 mutations refine prognostic stratification of IDH-wildtype astrocytomas, not elsewhere classified.}},
author = {Nayuta Higa and Toshiaki Akahane and Seiya Yokoyama and Taiji Hamada and Hajime Yonezawa and Ryutaro Makino and Tomoko Takajo and Mari Kirishima and Ikumi Kitazono and Yutaka Fujioka and Ryusuke Hatae and Daisuke Kuga and Shohei Nagasaka and Kohei Suzuki and Junkoh Yamamoto and Koji Yoshimoto and Akihide Tanimoto and Ryosuke Hanaya},
journal = {Acta neuropathologica communications},
year = {2026},
month = aug,
doi = {10.1186/s40478-026-02397-6},
url = {https://europepmc.org/article/MED/42958462},
note = {CC BY},
}
RIS
TY - JOUR
TI - EGFR and TP53 mutations refine prognostic stratification of IDH-wildtype astrocytomas, not elsewhere classified.
AU - Nayuta Higa
AU - Toshiaki Akahane
AU - Seiya Yokoyama
AU - Taiji Hamada
AU - Hajime Yonezawa
AU - Ryutaro Makino
AU - Tomoko Takajo
AU - Mari Kirishima
AU - Ikumi Kitazono
AU - Yutaka Fujioka
AU - Ryusuke Hatae
AU - Daisuke Kuga
AU - Shohei Nagasaka
AU - Kohei Suzuki
AU - Junkoh Yamamoto
AU - Koji Yoshimoto
AU - Akihide Tanimoto
AU - Ryosuke Hanaya
PY - 2026
DA - 2026/08/03
JO - Acta neuropathologica communications
DO - 10.1186/s40478-026-02397-6
UR - https://europepmc.org/article/MED/42958462
AB - IDH-wildtype astrocytomas of histological grade 2 or 3 without the WHO 2021 molecular criteria for glioblastoma-TERT promoter mutation, EGFR amplification, or combined whole-chromosome 7 gain and 10 loss (+ 7/- 10)-are designated "Not Elsewhere Classified" (NEC), a residual category with clinical behavior ranging from indolent disease to courses clinically indistinguishable from glioblastoma (GBM). However, reliable molecular markers capable of resolving this heterogeneity have not been established. We retrospectively profiled a multi-institutional cohort comprising 38 adult IDH-wildtype astrocytoma NEC cases and 429 GBM controls using a bimodal DNA/RNA next-generation sequencing panel and, in 30 NEC cases, genome-wide DNA methylation profiling. NEC tumors were markedly heterogeneous: 21 of the 30 methylation profiles (70%) failed to match any reference class family, and the remaining nine were distributed across six categories, with Uniform Manifold Approximation and Projection (UMAP) showing scattered embedding adjacent to multiple high- and low-grade reference clusters, rather than a coherent NEC cluster. Against this heterogeneous background, two point mutations emerged as candidate markers for aggressive disease: EGFR mutations (3/38, 7.9%), all clustered in the extracellular domain, and TP53 mutations (8/38, 21.1%), predominantly in the DNA-binding domain. Both retained independent prognostic significance in Firth-penalized multivariate Cox regression (EGFR: HR 1.61, 95% CI 1.02-2.57, P = 0.028; TP53: HR 1.55, 95% CI 1.00-2.42, P = 0.041). NEC patients harboring EGFR and/or TP53 mutations showed an overall survival curve closely paralleling that of GBM (P = 0.9605) and significantly diverged from EGFR/TP53-wildtype NEC (P = 0.0011). Thus, despite the marked genomic and epigenomic heterogeneity within NEC, EGFR and TP53 point mutations may identify a high-risk NEC subgroup. This stratifier is deployable with routine targeted sequencing panels already widely used in diagnostic practice, and provides a practical refinement complementary to the cIMPACT-NOW Update 11 framework, pending prospective validation.
SN - 2051-5960
ER -