Glioblastoma (GBM) is the most aggressive and common type of primary malignant brain tumor in adults. This fast-growing cancer originates from astrocytes, the star-shaped glial cells that provide structural support to neurons. Glioblastoma is relatively rare, with an incidence rate of about three individuals per 100,000 people per year. Despite multidisciplinary treatments, the prognosis is poor, with a median survival time of around 15 months.
Understanding Sporadic Versus Inherited Glioblastoma
The overwhelming majority of glioblastoma cases (over 90%) are sporadic, meaning they are not inherited. Sporadic glioblastoma arises from genetic changes, or somatic mutations, that occur randomly in brain cells during a person’s lifetime. These acquired alterations are confined to the tumor cells and are not present in the person’s reproductive cells.
The development of sporadic glioblastoma involves the accumulation of these somatic mutations, often related to natural processes like aging. This genetic damage disrupts the normal cell cycle and growth control mechanisms within the astrocyte cells. Primary glioblastoma typically occurs in older adults, with a median age of diagnosis around 64 years. It develops de novo, meaning it arises directly from glial cells without evolving from a lower-grade tumor over time.
Inherited glioblastoma involves a germline mutation, which is a genetic change present in every cell of the body. This mutation can be passed from a parent to a child, leading to a hereditary cancer syndrome. Inherited cases account for less than 10% of all glioblastomas. When glioblastoma is inherited, it is typically part of a well-defined genetic syndrome that predisposes the individual to multiple types of cancer.
Specific Hereditary Conditions That Increase Risk
Rare hereditary conditions significantly increase an individual’s lifetime risk of developing glioblastoma. These genetic syndromes involve specific inherited germline mutations in tumor-suppressor genes or DNA repair pathways. These syndromes account for the small fraction of inherited glioblastoma cases.
One recognized condition is Li-Fraumeni Syndrome, caused by an inherited mutation in the TP53 gene. This gene provides instructions for a protein that acts as a tumor suppressor, helping to repair damaged DNA or trigger cell death. When TP53 is mutated, the protein is non-functional, leading to a high lifetime risk of multiple cancers, including brain tumors, sarcomas, and breast cancer, often diagnosed at a young age.
Another established condition is Neurofibromatosis Type 1 (NF1), which results from a mutation in the NF1 gene. The protein produced by this gene, neurofibromin, also functions as a tumor suppressor, regulating cell growth and division. Individuals with NF1 are predisposed to various tumors, including gliomas that may progress to glioblastoma. Other syndromes, such as Turcot syndrome and Tuberous Sclerosis, are also associated with an elevated risk of glioblastoma.
Established Environmental Risk Factors
The most consistently identified non-hereditary factor increasing glioblastoma risk is exposure to high-dose ionizing radiation. This exposure typically results from prior therapeutic radiation treatments directed at the head or neck for other types of cancer. While rare, developing a secondary glioblastoma following radiation is a well-documented cause of cancer development years after the initial treatment.
Advanced age is another prominent risk factor for sporadic glioblastoma, with incidence rising dramatically in individuals over 50. The median age of diagnosis is 64, which suggests that the cumulative effects of cellular damage and the natural decline in DNA repair mechanisms over a lifetime contribute to tumor formation. Male sex also shows an association, with males having a higher incidence rate than females. Theories linking glioblastoma to common environmental exposures, such as cell phone use, have not been substantiated by convincing scientific evidence.
When to Consider Genetic Counseling
Individuals concerned about their personal or family history of glioblastoma should consult a genetic counselor for a structured risk assessment. This professional evaluation is warranted when there is a significant pattern of cancer suggesting an underlying hereditary syndrome. A key indicator is the diagnosis of glioblastoma in multiple close relatives, such as a parent and a sibling, or in two or more first- or second-degree relatives.
Counseling is also strongly recommended when glioblastoma is diagnosed at a very young age, or when a family history includes a combination of tumors associated with a specific syndrome, such as brain tumors paired with sarcomas, adrenal cancers, or breast cancers. The process involves the counselor constructing a detailed family pedigree to identify patterns and discussing the potential for germline testing. Genetic testing, which is often performed first on the affected family member, helps determine if a specific inherited mutation is present, clarifying the risk for other family members.