Glioblastoma, IDH-wildtype

107 Central Nervous System Tumours (WHO Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Jieying Chu, PhD

WHO Classification of Disease

Structure	Disease
Book	Central Nervous System Tumours (5th ed.)
Category	Gliomas, glioneuronal tumours, and neuronal tumours
Family	Gliomas, glioneuronal tumours, and neuronal tumours
Type	Adult-type diffuse gliomas
Subtype(s)	Glioblastoma, IDH-wildtype

Related Terminology

Acceptable	N/A
Not Recommended	Glioblastoma multiforme

Gene Rearrangements

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Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
FGFR3	FGFR3::TACC3	Constitutive activation of FGFR3 tyrosine kinase through fusion with TACC3, resulting in persistent MAPK and PI3K pathway signaling (PMID: 33168106).	Intrachromosomal tandem duplication at 4p16.3 (PMID: 33168106).	Recurrent (~3–5%) in IDH-wildtype glioblastoma (PMID: 33168106).	D, T	Yes (WHO CNS; NCCN)	FGFR3::TACC3 is a recurrent and characteristic fusion in IDH-wildtype glioblastoma and defines a molecular subset of tumors (PMID: 33168106). The fusion has diagnostic utility in confirming IDH-wildtype status in the appropriate histologic context (PMID: 29718398). Clinical responses to FGFR inhibitors have been reported, though therapeutic benefit in glioblastoma remains under investigation (PMID: 33168106).
NTRK1 / NTRK2 / NTRK3	ETV6::NTRK3, BCAN::NTRK1, TPM3::NTRK1, others (PMID: 29718398)	Constitutive TRK kinase activation caused by fusion-driven ligand-independent signaling (PMID: 32665022).	Variable inter- and intrachromosomal rearrangements (PMID: 29718398)	Rare (<5%), typically ≤2% of glioblastomas (PMID: 32665022).	D, T	Yes (NCCN; FDA tumor-agnostic approval)	NTRK fusions are rare but clinically actionable in glioblastoma. TRK inhibitors (e.g., larotrectinib, entrectinib) have demonstrated durable responses in NTRK fusion–positive tumors, including CNS neoplasms (PMID: 32665022). Prognostic significance in glioblastoma remains unclear due to low frequency.
MET	PTPRZ1::MET, ST7::MET, CAPZA2::MET, others (PMID: 29718398).	Fusion-mediated constitutive MET tyrosine kinase activation with downstream oncogenic signaling (PMID: 32761533).	Variable, often complex rearrangements (PMID: 29718398).	Rare (<5%), reported in ~2–3% of IDH-wildtype glioblastomas (PMID: 32761533).	D, T (emerging)	No	MET fusions, particularly PTPRZ1::MET, have been associated with aggressive clinical behavior and shorter progression-free survival in IDH-wildtype glioblastoma (PMID: 32761533). Therapeutic targeting of MET in this setting remains investigational.
ROS1	GOPC::ROS1, other rare partners (PMID: 31292243).	Constitutive ROS1 kinase activation resulting from fusion events (PMID: 31292243).	Variable chromosomal rearrangements (PMID: 31292243).	Rare (<5%), estimated <1% of adult glioblastomas (PMID: 31292243).	D, T (emerging)	No	ROS1 fusions are rare in glioblastoma but represent a potentially actionable alteration. Isolated case reports describe responses to ROS1 inhibitors such as entrectinib in ROS1-rearranged gliomas (PMID: 31292243).
EGFR	Structural rearrangements (e.g., EGFR::SEPT14, other EGFR fusions) (PMID: 29681515).	Aberrant EGFR signaling due to structural rearrangements or fusion events, promoting tumor growth and survival (PMID: 29681515).	Complex rearrangements involving chromosome 7p11.2 (PMID: 29681515).	Rare (<5%) for EGFR fusions; EGFR alterations overall are common in glioblastoma (PMID: 29681515).	D	Yes (WHO CNS)	EGFR structural rearrangements are part of the molecular spectrum of IDH-wildtype glioblastoma and contribute to diagnostic classification per WHO CNS criteria (PMID: 29681515). Targeted EGFR therapies have not demonstrated consistent clinical benefit in glioblastoma.
BRAF	Rare BRAF fusion events with various partners (PMID: 29681515).	Fusion-mediated activation of the MAPK signaling pathway (PMID: 29681515).	Variable chromosomal alterations (PMID: 29681515).	Rare (<5%) in adult glioblastoma (PMID: 29681515).	D	No	BRAF fusions are uncommon in adult glioblastoma and are more characteristic of pediatric low-grade gliomas. Their clinical significance in glioblastoma remains limited (PMID: 29681515).

Individual Region Genomic Gain/Loss/LOH

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Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
7	Gain	Whole chromosome 7; chr7 [hg38]	EGFR, MET, CDK6	D, P	Yes (WHO CNS)	Gain of chromosome 7 is a hallmark cytogenetic abnormality of IDH-wildtype glioblastoma and, when combined with loss of chromosome 10, supports the diagnosis of glioblastoma in the appropriate histologic context (PMID: 29681515). Chromosome 7 gain often co-occurs with EGFR amplification and is associated with aggressive tumor behavior (PMID: 33168106).
10	Loss	Whole chromosome 10; chr10 [hg38]	PTEN	D, P	Yes (WHO CNS)	Loss of chromosome 10 is one of the most frequent alterations in IDH-wildtype glioblastoma and commonly accompanies chromosome 7 gain (PMID: 29681515). This alteration contributes to PTEN loss and PI3K pathway activation and is associated with poor prognosis (PMID: 33168106).
9	Loss / LOH	9p21.3; chr9:21,800,000–22,100,000 [hg38; ~0.3 Mb]	CDKN2A, CDKN2B	D, P	Yes (WHO CNS)	Homozygous deletion of CDKN2A/CDKN2B is a frequent event in IDH-wildtype glioblastoma and results in loss of cell cycle control (PMID: 29681515). CDKN2A homozygous deletion is recognized by WHO CNS as a molecular criterion supporting glioblastoma classification and is associated with adverse prognosis (PMID: 33168106).
12	Amp	12q14.1–q15; chr12:68,500,000–70,200,000 [hg38; ~1.7 Mb]	MDM2, CDK4	D, T	No	Amplification of MDM2 and/or CDK4 leads to dysregulation of the p53 and RB pathways and is recurrent in IDH-wildtype glioblastoma (PMID: 29681515). These amplifications may be mutually exclusive with CDKN2A deletion and are under investigation as potential therapeutic targets (PMID: 33168106).
13	Loss	13q14; chr13:48,000,000–50,000,000 [hg38; ~2 Mb]	RB1	P	No	Loss of chromosome 13q, including RB1, contributes to cell cycle deregulation in glioblastoma (PMID: 29681515). RB1 loss is associated with aggressive tumor behavior, though it is not independently diagnostic (PMID: 33168106).
19	Gain	19q12–q13; chr19 [hg38]	CCNE1, AKT2	P	No	Gain of chromosome 19 or 19q is observed in a subset of IDH-wildtype glioblastomas and may contribute to oncogenic signaling (PMID: 29681515). Unlike 1p/19q codeletion, isolated 19q gain has no defining diagnostic role in glioblastoma.
20	Gain	20q; chr20 [hg38]	AURKA	P	No	Gain of chromosome 20q has been reported as a recurrent secondary alteration in glioblastoma and may be associated with tumor progression (PMID: 33168106). Clinical significance remains limited.

Characteristic Chromosomal or Other Global Mutational Patterns

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Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

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References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): *Citation of this Page: “Glioblastoma, IDH-wildtype”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/30/2025, https://ccga.io/index.php/CNS5:Glioblastoma, IDH-wildtype.