Glioblastoma is the most common and aggressive primary brain cancer in adults. It grows rapidly and infiltrates surrounding brain tissue, making it difficult to treat. For a long time, it was viewed as a single, uniform disease, but scientific advancements have revealed distinct subtypes with unique characteristics. This discovery is changing how glioblastoma is understood and managed, moving away from a one-size-fits-all approach to a more personalized strategy.
The Shift to Molecular Classification
The method for classifying glioblastoma has undergone a significant evolution. Traditionally, pathologists classified these tumors based on their histological features, observing the appearance and structure of cancer cells under a microscope. This approach provided an initial diagnosis but offered limited insight into a tumor’s specific behavior or how it might respond to treatment.
A major shift occurred with the move toward molecular classification, a process that analyzes a tumor’s specific genetic and molecular characteristics. This modern approach looks for “biomarkers,” which are specific gene mutations or changes in protein expression that define the tumor on a biological level. The World Health Organization (WHO) has championed this molecular classification, recognizing that it offers a more accurate prediction of the tumor’s behavior and prognosis than histology alone.
This transition from what a tumor looks like to what it is on a genetic level marks a change in neuro-oncology. By identifying the molecular drivers of a tumor, clinicians gain a clearer understanding of its potential trajectory. This detailed molecular fingerprint allows for a more refined diagnosis and is the foundation for developing targeted treatment strategies.
IDH-Wildtype vs. IDH-Mutant Glioblastoma
The most fundamental distinction in modern glioblastoma classification is based on the status of the isocitrate dehydrogenase (IDH) gene. Tumors are categorized into two main groups: IDH-wildtype and IDH-mutant. This single genetic difference separates glioblastoma into two diseases with vastly different behaviors and outcomes, forming the basis of the current WHO classification system.
IDH-wildtype glioblastoma is the most common form, accounting for approximately 90% of all cases. It is considered a “primary” glioblastoma, meaning it arises spontaneously, typically in older adults with a mean age of diagnosis around 62. These tumors are characterized by rapid growth and infiltration of brain tissue, and the prognosis is generally poor with a median survival of around 15 months with treatment.
In contrast, IDH-mutant glioblastoma is less common and tends to be diagnosed in younger patients, often under the age of 55. These tumors are “secondary,” meaning they evolve from a pre-existing, lower-grade astrocytoma over several years. Although still a grade 4 tumor, the presence of the IDH mutation is associated with a significantly better prognosis. Patients with IDH-mutant glioblastoma have a longer median survival, which can extend to 31 months or more. This distinction underscores why molecular testing is now standard practice.
Significant Biomarkers Within Subtypes
Beyond the primary IDH classification, other molecular markers provide a more detailed profile of a glioblastoma tumor. One of the most significant is the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter. The MGMT gene codes for a protein that repairs DNA damage. When the promoter region of this gene is methylated, it is “turned off,” preventing the production of the repair protein.
This inactivation of the MGMT gene is a predictive biomarker, as its status indicates how a tumor will likely respond to certain chemotherapy. A methylated MGMT promoter means the tumor cells cannot repair the DNA damage caused by alkylating agents like temozolomide (TMZ). This makes the tumor more susceptible to the treatment, so testing for MGMT promoter methylation is a standard part of the diagnostic process.
Other molecular markers also contribute to a tumor’s complete profile. Amplification of the epidermal growth factor receptor (EGFR) gene is a common feature in IDH-wildtype tumors and is associated with aggressive growth. Mutations in the TERT promoter are also frequent in IDH-wildtype glioblastoma and are linked to more aggressive tumor behavior. These markers provide valuable prognostic information and help clinicians build a comprehensive molecular picture of an individual’s disease.
How Subtyping Guides Treatment and Prognosis
The molecular subtype of a glioblastoma directly influences a patient’s treatment plan and provides a clearer understanding of their prognosis. Knowing the tumor’s specific genetic profile allows oncologists to move beyond a generalized approach and tailor therapies to the individual. This personalized strategy is based on the unique biological characteristics of the tumor, which can predict its behavior.
The IDH mutation status is an important prognostic tool. A diagnosis of IDH-mutant glioblastoma indicates a more favorable outcome with longer overall survival compared to IDH-wildtype glioblastoma. This information helps doctors and patients understand the likely course of the disease and can influence the aggressiveness of the treatment strategy.
Furthermore, a detailed molecular profile, including markers like EGFR and TERT, can make a patient eligible for specific clinical trials. These trials investigate targeted therapies designed to attack tumors with those particular alterations.