Glioblastoma is an aggressive form of brain cancer. To better understand and combat this disease, scientists rely on molecular markers, which are distinct biological characteristics found within the tumor cells. Identifying these molecular signatures provides insights that can shape diagnosis, treatment plans, and patient prognosis.
The Process of Identifying Markers
Uncovering a glioblastoma’s molecular profile begins with acquiring tumor tissue through a surgical biopsy or resection. This tissue is sent to a pathologist to confirm the diagnosis, then to a specialized laboratory for molecular testing. Technicians use methods like next-generation sequencing (NGS) to analyze the tumor’s DNA, RNA, and proteins.
This analysis detects specific mutations and other changes that define the tumor’s molecular identity. A less invasive method being developed is the liquid biopsy, which analyzes tumor-derived DNA in fluids.
Key Molecular Markers in Glioblastoma
Several molecular markers are significant in understanding glioblastoma. These markers are now routinely tested for as they are integrated into the official classification of these tumors.
IDH (Isocitrate Dehydrogenase) Mutation
Isocitrate dehydrogenase (IDH) is an enzyme involved in cell metabolism. In some glioblastomas, the IDH1 or IDH2 gene is mutated, dividing tumors into two categories: IDH-mutant and IDH-wildtype (no mutation). IDH-mutant tumors are considered secondary, often evolving from lower-grade gliomas. The more common IDH-wildtype tumors are typically primary, arising without a preceding lower-grade tumor.
MGMT (O-6-methylguanine-DNA methyltransferase) Promoter Methylation
MGMT is a protein that repairs damaged DNA. Its production is controlled by a promoter region that can undergo a chemical change called methylation, which silences the MGMT gene. When the promoter is methylated, the tumor cells cannot produce the MGMT repair protein. This leaves them unable to fix certain types of DNA damage.
TERT Promoter Mutation
The TERT gene codes for a component of telomerase, an enzyme that maintains protective caps (telomeres) at the ends of chromosomes. In normal cells, telomeres shorten with each division, acting as a brake on replication. A mutation in the TERT promoter can lead to the overexpression of telomerase, allowing cancer cells to rebuild their telomeres and divide limitlessly. This mutation is found in approximately 70-80% of primary glioblastomas.
EGFR (Epidermal Growth Factor Receptor) Amplification
The epidermal growth factor receptor (EGFR) is a protein on the cell surface that signals the cell to grow and divide. In many glioblastomas, the EGFR gene is amplified, creating too many copies of the gene and an excessive number of EGFR proteins. As a result, the cells become overstimulated by growth signals, leading to uncontrolled proliferation. This alteration is one of the most common genetic abnormalities in IDH-wildtype glioblastoma.
How Markers Guide Treatment Strategies
Knowledge of a glioblastoma’s molecular marker status is indispensable for tailoring treatment plans. This personalized approach allows oncologists to move beyond a one-size-fits-all strategy and select therapies that are more likely to be effective against a specific patient’s tumor.
The MGMT promoter status is a direct guide for chemotherapy selection. The standard chemotherapy, temozolomide (TMZ), works by damaging cancer cell DNA. If a tumor has a methylated MGMT promoter, it cannot produce the repair protein to fix this damage, making the cells highly susceptible to TMZ. Tumors with an unmethylated promoter can repair the damage, often leading to drug resistance.
The presence of EGFR amplification also influences therapeutic considerations. Because EGFR drives tumor growth, it is a target for drugs known as tyrosine kinase inhibitors (TKIs). While the success of these therapies in glioblastoma has been limited, EGFR amplification can make a patient eligible for clinical trials investigating new EGFR inhibitors.
The discovery of IDH mutations has also opened avenues for targeted therapies. The mutant IDH enzyme can be targeted by specific drugs, leading to the development of IDH inhibitors. These are being investigated in clinical trials and may offer a therapeutic option for patients with IDH-mutant tumors.
The Prognostic Significance of Markers
Beyond guiding treatment, molecular markers provide prognostic information, helping to predict the likely course of the disease. This information is valuable for both clinicians and patients in setting expectations and planning for the future.
The most significant prognostic marker is the IDH mutation status. Patients with IDH-mutant glioblastoma generally have a more favorable prognosis compared to those with IDH-wildtype tumors. The median survival for patients with IDH-mutant tumors is substantially longer, even though both are classified as the same grade of cancer.
The methylation status of the MGMT promoter also carries strong prognostic weight. Patients with a methylated MGMT promoter tend to have better outcomes, partly because their tumors respond more effectively to temozolomide. MGMT methylation is also a favorable prognostic factor independent of treatment. The combination of an IDH mutation and MGMT methylation is associated with the most favorable prognosis. Conversely, TERT promoter mutations and EGFR amplification are linked to more aggressive tumor behavior.