Genomic Research on Gliomas

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Mar 10, 2026 04:50 PM

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I. Overview

Glioblastoma	Description
Classification	LGG I, II, III GBM IV Average survival 18 months (most malignant)
Region	Predominantly in Europe and America
Most malignant	Incidence trending upward, affecting younger age groups
Tumor Category	Low-incidence tumors (fewer patients)
Surgical Treatment	Wide excision
Drug Therapy	Very few drugs available; only TM2 can extend survival by 6 months Reason for limited drugs: Blood-brain barrier
Our Research	Wang Xiuxing/Wang Qianghu
Origin	Astrocytes, oligodendrocytes, ependymal cells

II. Epidemiological Characteristics

2.1 Issues

Low incidence; classification challenges exist

Diversity of subtypes (pathological classification/subtypes)

Difficulties in standardization (varying criteria)

Significant Variation in Diagnostic Protocols

Technology

Regional variations in evaluation protocols

Diagnostic sensitivity bias

Tumor heterogeneity

Different tumor types are often grouped together

May miss associations with subtypes

TCGA Cancer/TCGA Brain Glioma

2.2 Age and Gender Characteristics

Age: Incidence increases after age 35, continues to rise until age 80, then shows a declining trend;

Gender: Incidence is slightly higher in males than females, approximately 1.6 times that of females.

2.3 Geographic Distribution

Higher incidence in Europe and America

2.4 Risk Factors

Risk factors for glioma: Causes are unknown

Neurofibromatosis

• NF-1 and NF-2

Von Hippel-Lindau syndrome

• VHL

Li-Fraumeni syndrome

• TP53

Turcot's syndrome

• APC

Basal cell nevus syndrome (Gorlin syndrome)

• PTCH

Familial glioma

2.5 GWAS Screening

Genetic variants - GWAS (GWAS screening)

Two groups using GWA approaches identified novel glioma susceptibility genes

UK/US study - 521,318 SNP genotypes in 1,878 cases and 3,670 controls for discovery, with candidates replicated in 3 independent sets

5 loci - TERT, CDKN2A/CDKN2B, RTEL1, PHLDB1, CCDC26

UCSF/TCGA/Mayo - 275,895 variants in 692 cases and 3,992 controls with candidates replicated in an independent set

2 loci - RTEL1 and CDKN2B

(Uncontrolled cell amplification)

2.6 Occupational Exposure/Risk Factors

Occupational exposure: (Some studies exist, but no direct strong evidence)

Vinyl chloride

Refineries and petroleum processing plants

Agricultural exposure (pesticides, herbicides, fungicides)

Engaging in agriculture or residing on farms (farmers) has been found to increase the risk of brain tumors. A meta-analysis of 33 studies suggests that farmers have a 1.3-fold increased risk of brain tumors, but the specific chemical responsible for carcinogenesis remains unclear.

Radiation

Ionizing radiation: Induces genomic mutations; when DNA breaks, it repairs itself, but mutations occur during this process. Generates ROS, leading to oxidative stress. At high concentrations, it produces oxidative free radicals that break DNA strands, but not continuously—only continuous exposure causes breaks.

Medical Diagnostics: CT and contrast-enhanced CT (brain), chest X-rays are instantaneous

Atomic bomb survivors

High-frequency radiation: Cell phones??

Ultraviolet Sterilization (not disinfection) Blue Light: Attracts flies UV Light: 30-minute exposure breaks DNA, primarily targeting bacteria Additionally, ozone production enables oxidation

1 0,834 patients treated with radiation for tinea capitis (scalp ringworm) between 1948-1960

Mean 1.5 Gy exposure to the brain surface (Average 1.5 Gy exposure to the brain surface)

Increased relative risk for:

Meningioma 9.5 (n=19)

Glioma 2.6 (n=7) (Glioma 2.6 (n=7))

Nerve sheath tumors 18.8 (n=25)

(nerve sheath tumors 18.8 (n=25))

A dose-response relationship was identified with RR approaching 20 for exposure to 2.5 Gy

Tobacco: No direct association

Tobacco: No direct association

Alcohol: Most studies show no association

Diet:

Nitrosamines: Exposure is a risk factor for glioma; antioxidant intake may reduce glioma risk;

Red meat: Increases glioma risk by 48%.

III. Clinical Characteristics

3.1 Classification Systems

Based on tumor growth patterns, gliomas can be classified into two categories:

Focal Glioma (Pilocytic Astrocytoma)

Diffuse glioma According to

WHO Classification of Tumors of the Central Nervous System (2007, 4th Edition)

Diffuse gliomas are graded as II, III, and IV

Pathologically:

Diffuse astrocytoma (WHO Grade II) exhibits abundant proliferating glial fibers with mild to moderate nuclear atypia and prominent mitotic activity. Oligodendroglioma (WHO Grade III) presents with well-defined cell borders, clear cytoplasm, and centrally located round nuclei arranged in a honeycomb pattern.

Anaplastic oligodendroglioma (WHO Grade III) exhibits marked nuclear atypia and vascular proliferation.

GBM (glioblastoma multiforme, WHO Grade IV),

as the most aggressive glioma,

exhibits abundant tumor tissue with large cells, marked nuclear atypia, frequent mitotic figures, proliferating vascular endothelium , and numerous immature vessels (impairing nutrient transport). It may be associated with extensive hemorrhage (due to vascular immaturity) and necrosis.

Primary GBM predominantly affects middle-aged and elderly patients over 55 years old, while secondary GBM, arising from low-grade gliomas, occurs in patients younger than 55 and accounts for 5%–10% of GBM cases.

3.2 ★ Molecular Biomarkers of Gliomas (Red text must be memorized in full)

Highly recommended

Glial fibrillary acidic protein (GFAP):

Expressed in gliomas with astrocytic differentiation characteristics and 60–70% of oligodendrogliomas (Grade I evidence)

Isocitrate dehydrogenase 1 (IDH1):

Homozygous mutations at IDH1 position 132 are present in over 80% of low-grade gliomas (e.g., astrocytomas, oligodendrogliomas, mixed oligodendrogliomas, and secondary glioblastomas) (Level I evidence)

Ki-67: One of the key prognostic indicators for tumors (Level I evidence) Proliferation-related

Chromosomal 1p/19q loss of heterozygosity (1p/19q LOH): A molecular genetic hallmark of oligodendroglioma (Level I evidence).

Oligodendrocyte-specific nuclear transcription factor (Olig2): Primarily expressed in oligodendrocyte nuclei.

Epidermal membrane antigen (EMA): Expressed on normal epithelial cell membranes and tumors of epithelial or mesothelial origin, such as ependymomas;

p53 protein: TP53 gene mutation rates exceed 65% in gliomas of astrocytic origin or secondary glioblastomas (Level II evidence);

Epidermal Growth Factor Receptor vIII (EGFRvIII): Detection of high-grade gliomas using specific EGFRvIII monoclonal antibodies serves as a breakthrough for targeted therapy and is clinically applied (Level III evidence).

O6-methylguanine-DNA methyltransferase (MGMT): MGMT testing in glioblastoma predicts patient prognosis.

Neuron-specific nuclear protein (NeuN): Primarily used for diagnosis and differential diagnosis of glial neuronal tumors and neuroblastomas.

KIAA1549-BRAF fusion gene: Detection rate in pilocytic astrocytomas is approximately 60%–80%.

Molecular Biomarkers	Function
Glial fibrillary acidic protein (GFAP)	Expressed in gliomas with astrocytic differentiation characteristics and 60%–70% of oligodendrogliomas (Grade I evidence)
Isocitrate dehydrogenase 1 (IDH1)	Heterozygous mutations at position 132 of the IDH1 gene are present in over 80% of low-grade gliomas (e.g., astrocytomas, oligodendrogliomas, mixed oligodendrogliomas, and secondary glioblastomas) (Level I evidence)
Ki-67	One of the key prognostic indicators for tumors (Level I evidence) Proliferation-related
Chromosomal 1p/19q heterozygous loss(1p/19q LOH)	A molecular genetic feature ofoligodendroglioma(Level I evidence).
Oligodendrocyte-specific nuclear transcription factor (Olig2)	Primarily expressed in oligodendrocyte nuclei;
Epidermal membrane antigen (EMA)	Distributed in normal epithelial cell membranes and tumors of epithelial or mesothelial origin, such as ependymomas;
p53 protein	In astrocytic-origin gliomas or secondary glioblastomas, TP53 gene mutation rates exceed 65% (Level II evidence);
Epidermal Growth Factor Receptor vIII (EGFRvIII)	Detected using specific EGFRvIII monoclonal antibodies in high-grade gliomas, serving as a breakthrough for targeted therapy and currently applied clinically (Level III evidence).
O6-methylguanine-DNA methyltransferase (MGMT)	MGMT detection in glioblastoma. Predicts patient prognosis.
Neuron-specific nuclear protein (NeuN)	Primarily used for diagnosis and differential diagnosis of glial neuronal tumors and neuroblastomas.
KIAA1549-BRAF fusion gene	Detection rate in pilocytic astrocytomas is approximately 60%–80%.

3.3 Glioma Grading

Seven fundamental principles for glioma grading:

Tumor cell density

Proliferative capacity

High nuclear atypia or anaplasia, with multinucleated and giant nuclei

High mitotic activity

Vascular endothelial cell proliferation (with glomerular-like vascular proliferation)

Necrosis (pseudogranular necrosis)

Elevated proliferation index

3.4 Flowchart

3.5 Surgical Strategy

Maximally safe tumor resection:(preferred)

Indications: Primary high-grade gliomas (WHO III–IV) and low-grade gliomas (WHO II) confined to a cerebral lobe

Microsurgical techniques are recommended to achieve maximal tumor resection with minimal tissue and neurological compromise, confirming histopathological diagnosis.

Partial tumor resection, craniotomy biopsy, or stereotactic (or navigation-guided) needle biopsy:

Indications: Diffusely infiltrative growth in the dominant hemisphere, bilateral involvement, elderly patients (>65 years), poor preoperative neurological status (KPS < 70), deep-seated or brainstem-located malignant gliomas, and gliomatosis cerebri.

High-grade gliomas—primarily recommended

Timing of radiotherapy:

HGG includes glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma. Radiotherapy should commence as early as possible postoperatively.

Target Volume and Dose:

GTV: Postoperative residual tumor and/or surgical cavity as demonstrated on MRI T1-weighted contrast-enhanced images.

CTV1: 2 cm expansion around GTV, dose 46–50 Gy.

CTV2: 1 cm beyond the GTV, receiving a dose of 10–14 Gy.

Concurrent Chemoradiotherapy:

Temozolomide (TMZ) 75 mg/m² administered concurrently with radiotherapy, followed by 6 cycles of adjuvant TMZ chemotherapy.