Glioblastoma has no single known cause, and the majority of cases appear without any identifiable risk factor. Unlike many cancers tied to smoking, diet, or specific infections, glioblastoma develops from a series of genetic errors inside brain cells that researchers still don’t fully understand. What is known involves a combination of cell biology, a short list of confirmed risk factors, and several things that have been ruled out.
How Glioblastoma Starts in the Brain
The brain contains stem cells and precursor cells that normally help maintain and repair tissue. Glioblastoma is thought to begin when some of these cells accumulate mutations that disable their normal growth controls. The adult brain harbors stem cells in a region called the subventricular zone, located near the fluid-filled ventricles deep in the brain. In animal models, tumors resembling glioblastoma can be induced directly from these stem cells when key tumor-suppressing genes are knocked out.
Not all glioblastomas start in the same place. Some tumors clearly originate from those deep stem cell regions and tend to grow in ways that spread across wide areas of the brain. Others appear to arise from precursor cells scattered throughout brain tissue, far from the subventricular zone. This variation in origin helps explain why glioblastomas can show up in different locations and behave somewhat differently from patient to patient, even though they carry the same diagnosis.
The Genetic Errors That Drive Growth
Several specific mutations show up repeatedly in glioblastoma tumors, and together they paint a picture of how healthy cells lose control. Under the current WHO classification system (updated in 2021), glioblastoma is defined as a tumor that lacks a mutation in the IDH gene, which separates it from slower-growing brain tumors that do carry that mutation. Beyond that distinction, three molecular changes independently mark a tumor as the highest grade: mutations in the TERT gene promoter, amplification of the EGFR gene, and a pattern of gaining an extra copy of chromosome 7 while losing chromosome 10.
The TERT mutation is especially telling. Normally, your cells have a built-in clock: the protective caps on the ends of chromosomes (telomeres) shorten each time a cell divides, eventually triggering the cell to stop dividing and age out. TERT mutations flip this system off. They boost the activity of an enzyme that rebuilds those chromosome caps, effectively giving tumor cells unlimited ability to keep dividing. This mutation appears in glioblastoma more frequently than in most other cancers.
EGFR amplification works differently. The EGFR gene tells a cell to grow and divide in response to signals from its environment. When a cell carries extra copies of this gene, it becomes hypersensitive to growth signals, or even generates its own. Other common changes include the deletion of a gene called CDKN2A, which normally acts as a brake on cell division, and alterations to a DNA repair gene (MGMT) that can affect how the tumor responds to treatment.
None of these mutations are inherited in typical cases. They arise spontaneously within brain cells over a person’s lifetime, which is part of why glioblastoma remains so difficult to predict or prevent.
Confirmed Risk Factors
Only two risk factors have strong, consistent evidence behind them: ionizing radiation exposure and age.
Ionizing radiation, the type used in radiation therapy for cancer, is the clearest environmental risk factor. People who received radiation to the head or neck during childhood, often for leukemia or other childhood brain tumors, face an increased risk of developing glioblastoma later in life. This is not the same type of radiation emitted by cell phones or microwaves. It refers specifically to high-energy radiation capable of directly damaging DNA.
Age is the strongest demographic predictor. Glioblastoma is predominantly a disease of older adults, with most diagnoses occurring after age 50. Men are roughly 60% more likely to develop it than women, based on incidence data spanning 2000 to 2014 published in JAMA Oncology. The tumor is also most common in non-Hispanic white populations, occurring at a rate of about 4.7 per 100,000 people per year in that group, compared to roughly 1.9 per 100,000 in American Indian or Alaska Native populations. The reasons behind these demographic differences remain unclear.
Rare Hereditary Syndromes
A small fraction of glioblastoma cases occur in people with inherited genetic syndromes that broadly raise cancer risk. Li-Fraumeni syndrome, caused by mutations in the TP53 tumor suppressor gene, is the most well-known example. People with this condition face elevated risks for many cancer types throughout their lives, including high-grade brain tumors.
Other rare conditions linked to glioblastoma include melanoma-astrocytoma syndrome, which can produce brain tumors ranging from low-grade to glioblastoma, and Fanconi anemia, a DNA repair disorder where rare cases of glioblastoma have been reported. These hereditary causes account for a very small percentage of all diagnoses. The vast majority of glioblastoma patients have no family history of the disease and no identifiable inherited predisposition.
What About Cell Phones and Chemical Exposures?
Cell phone use is the most commonly asked-about environmental factor, and the evidence consistently points away from a meaningful link. A large Danish study tracking over 358,000 cell phone subscribers found no increased risk of glioma, even among people who had used phones for more than 10 years. The largest international study on the topic (Interphone) found no overall association, though it noted a slightly higher risk in the very heaviest users. However, when National Cancer Institute researchers compared the risk levels predicted by that finding against actual U.S. brain cancer rates from 1992 to 2008, the predicted increase never materialized. Brain cancer rates stayed flat during the same period cell phone use exploded across the population.
Occupational chemical exposures have also been investigated. A CDC-reviewed study of pesticide exposure, including insecticides and herbicides, found no association with glioma risk in either men or women. While isolated studies have occasionally flagged certain industrial chemicals, none have produced the kind of consistent, replicated evidence needed to establish a causal link.
Why Most Cases Have No Explanation
The uncomfortable reality of glioblastoma is that most people diagnosed with it did nothing to cause it and had no way to see it coming. The mutations that drive the tumor accumulate randomly in brain cells over decades. Some of this may relate to the inherent error rate of DNA replication: every time a cell divides, there is a small chance of a copying mistake, and over millions of divisions across a lifetime, harmful mutations occasionally land in the wrong combination of genes at the wrong time.
This concept, sometimes called “replicative luck,” has been proposed as a major factor in many cancers that lack clear environmental causes. It doesn’t mean nothing is happening biologically. It means the triggering events are so common and random at the cellular level that they don’t produce a pattern researchers can trace back to a preventable exposure. For glioblastoma in particular, the absence of modifiable risk factors is one of the reasons it remains among the most challenging cancers in oncology.