A brief introduction to gliomas

What are Gliomas?

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Gliomas are a group of brain tumors, which represent about 24.5% of all primary brain tumors and 80.9% of malignant brain tumors in adults.¹ Among those, glioblastoma multiforme is the most common subtype of glioma and the most common form of malignant brain tumor (~49%).² The median age at disease onset ranges from 43 years to 65 years, with glioblastoma typically affecting elderly patients and other forms of glioma peaking in young adults.¹ The incidence rate of glioma displays regional and ethnic variability and tends to be higher in males (5.51 per 100,000) than in females (3.65 per 100,000).¹

Overall survival rates depend strongly on the specific type of glioma and other factors such as age at disease onset and patient performance.³ Glioblastoma has the worst prognosis of all gliomas, with a 2-year survival rate of only ~14.8%.⁴ The only known causative environmental factor for glioma is previous exposure to ionizing radiation. However, certain genetic diseases, namely Li-Fraumeni syndrome, Turcot syndrome and neurofibromatosis type I are associated with an increased risk for developing glioma.¹ To this day, there is no known cure for glioma, and all gliomas eventually progress.^3,5

Classification and Molecular Markers

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According to the most recent guideline by the World Health Organization (WHO) from 2021, diffusely growing gliomas are categorized as either adult-type or pediatric-type (affecting mostly children, teenagers and young adults).⁶ Whereas adult-type diffuse gliomas are the most common form of primary malignant brain tumors, pediatric-type diffuse gliomas are much rarer.⁴ Adult-type diffuse gliomas are again subdivided into three distinct tumor entities: astrocytomas, oligodendrogliomas and glioblastomas.⁶ The classification of diffuse gliomas is based on an integration of histological features (e.g. necrosis, anaplasia, or vascular proliferation) and molecular alterations (point mutations, deletions and large structural variations). Within a given tumor subtype, tumor entities are graded with grades 1 to 4, which indicates an increasing degree of anaplasia and worsening clinical prognosis.⁶

The most significant molecular markers for glioma classification are the IDH1 and IDH2 genes. Point mutations in either one of these genes classifies a tumor as IDH-mutant or as IDH-wildtype if no mutations are found. The IDH mutational status divides the three types of adult diffuse gliomas into the IDH-mutant group, which consists of astrocytomas and oligodendrogliomas, and glioblastomas, which are IDH-wildtype.⁶ By far the most common type (~ 90%) of IDH-alteration is the R132H point mutation in the IDH1 gene caused by a CGT>CAT transition.⁷ The substitution of an arginine residue for a histidine residue in the catalytic site of isocitrate dehydrogenase 1 confers a novel activity to the enzyme, which now converts its former product α-ketoglutarate into D-2-hydroxyglutarate (2-HG). The accumulation of 2-HG leads to metabolic and epigenetic alterations, which most likely contributes to tumor development and growth.⁸ IDH mutational status is usually determined by immunostaining using antibodies against the R132H mutant IDH1 enzyme, or DNA sequencing.⁹

The distinction between the two IDH-mutant glioma subtypes, astrocytomas and oligodendrogliomas, is based on the presence of a complete co-deletion of chromosomal arms 1p and 19q. This 1p/19q co-deletion classifies an IDH-mutant glioma as an oligodendroglioma (grade 2 or 3), whereas the lack of a co-deletion classifies it as an astrocytoma (grade 2, 3 or 4).⁶ It is thought to arise from a translocation between chromosomes 1 and 19 near the centromeres, with subsequent loss of the derivative chromosome containing 1p and 19q.¹⁰ Detection of the 1p/19q co-deletion usually involves flourescence-in-situ-hybridization (FISH) analysis, PCR-based loss-of-heterozygosity analysis or array hybridization methods.¹¹ Other common genetic alterations found in oligodendrogliomas are activating mutations in the TERT promoter and mutations in the CIC and FUBP1 genes.⁶ Oligodendrogliomas tend to have the most favorable clinical outcomes among adult-type diffuse gliomas.⁴ Astrocytomas, which tend to have a worse prognosis than oligodendrogliomas, show frequent loss of nuclear ATRX expression and TP53 mutations.^4,6 If histopathological features of malignancy (necrosis or vascular proliferation) and/or a homozygous deletion of CDKN2A/B are present, astrocytomas are classified as grade 4, otherwise as grade 2 or 3.⁶

Glioblastomas, IDH-wildtype, are the most common type of glioma and the most common malignant brain tumor in adults, with the worst clinical prognosis.^1,4 Frequent molecular alterations include combined gain of chromosome 7 and loss of chromosome 10, TERT promoter mutations and amplifications of the epidermal growth factor receptor (EGFR) gene. EGFR amplifications are typically mediated through extrachromosomal DNA elements (double-minute chromosomes).¹² Amplifications are observed in more than 50% of glioblastoma cases, with 50-60% of these cases also showing expression of a constitutively activated form of EGFR, called EGFRvIII. This mutant receptor carries a deletion of exons 2-7 in its extracellular domain.^13,14 Diagnostic methods used to assess chromosomal +7/-10 alterations and EGFR amplifications are FISH and array hybridization methods.⁹

Treatment

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Standard treatment for all types of glioma includes maximal surgical resection of the tumor, if safely feasible.³ Post-operative treatment of IDH-mutant gliomas usually consists of radiotherapy followed by alkylating polychemotherapy (procarbazine, lomustine, vincristine) or temozolomide chemotherapy, depending on the type of glioma.³ The treatment strategy at progression or recurrence depends on the initial treatment strategy and response, and may include second surgery, re-irradiation, chemotherapy or experimental treatments.³ Chemo- and radiotherapy are usually associated with severe side-effects and toxicity, which leads to an additional reduction in the quality of life of glioma patients. Standard post-operative treatment for glioblastoma consists of radiotherapy and temozolomide chemotherapy followed by additional maintenance cycles of temozolomide. Response to temozolomide is largely limited to patients who harbor DNA methylations in the promoter region of the MGMT gene.^3,15 Its gene product, O6-methylguanine DNA methyltransferase, confers resistance to alkylating chemotherapy by removing alkyl groups from alkylated guanine bases.¹⁵ Thus, silencing methylations of the MGMT promoter might sensitize a tumor to temozolomide treatment.

To this date, no other treatment modalities have been able to significantly prolong the overall survival (OS) of glioblastoma patients.^3,15 Many experimental treatment approaches such as EGFR tyrosine kinase inhibitors, vaccines against EGFRvIII, PI3K inhibitors, or anti-VEGF antibodies (e.g. bevacizumab) have failed to show efficacy or prolong OS.¹⁵ Other experimental approaches to glioblastoma treatment are currently undergoing clinical trials and include oncolytic viral therapies, gene therapies using viral vectors, and different kinds of immunotherapies such as CAR-T cell therapies and immune checkpoint inhibitors.^15,16