Glioblastoma (GBM) is the most common and aggressive malignant brain tumor, characterized by rapid growth and poor prognosis. While this diagnosis is often devastating, the question of whether it can be passed down in families is a common concern. Most cases occur without clear genetic inheritance, but a small percentage of individuals diagnosed with GBM have an identifiable underlying genetic predisposition. Understanding the difference between these two forms is essential for accurate risk assessment and family planning.
Understanding the Difference Between Sporadic and Inherited Glioblastoma
Glioblastoma is categorized as either sporadic or inherited, based on the origin of the genetic change. Sporadic glioblastoma accounts for over 90% of all cases and occurs de novo, meaning the tumor arises without a predisposing genetic condition. The genetic changes are somatic mutations, acquired during a person’s lifetime and present only in the tumor cells. These acquired mutations result from damage or errors in cell division and cannot be passed down to children.
Inherited glioblastoma involves germline mutations, which are alterations present in every cell of the body, including sperm and egg cells. These mutations are passed down from a parent and significantly increase the lifetime risk of developing GBM and other cancers. This form represents a very small fraction (around 5%) of total GBM diagnoses. In these rare instances, the inherited mutation acts as a “first hit,” making cells vulnerable and requiring further acquired somatic mutations for the cancer to fully develop.
Identifying High-Risk Hereditary Syndromes
For the small number of hereditary glioblastoma cases, the risk is tied to specific, rare cancer predisposition syndromes. These syndromes involve germline mutations in genes that normally suppress tumors or repair damaged DNA. One condition is Neurofibromatosis Type 1 (NF1), caused by a mutation in the NF1 tumor suppressor gene. Individuals with NF1 have a heightened risk of developing various tumors, including low-grade optic nerve gliomas and high-grade gliomas.
Another risk factor is Li-Fraumeni Syndrome (LFS), which results from an inherited mutation in the TP53 tumor suppressor gene. LFS is associated with a high lifetime risk for multiple cancers, including sarcomas, breast cancer, and adrenocortical carcinoma, in addition to GBM. Since the TP53 gene regulates cell growth and programmed cell death, its inactivation predisposes the body to cancer development.
Turcot Syndrome is a third condition associated with a greater risk of GBM, often representing a form of Lynch Syndrome or Familial Adenomatous Polyposis (FAP). When linked to Lynch Syndrome, the cause involves germline mutations in mismatch repair (MMR) genes, such as MLH1 or MSH2. These genes correct errors during DNA replication; a defect leads to genomic instability and a higher risk for cancers, including gliomas, typically alongside colorectal cancer.
When to Seek Genetic Counseling and Testing
Since most glioblastomas are sporadic, genetic counseling is generally recommended only when personal or family history suggests a hereditary syndrome. A referral is appropriate if a person is diagnosed with GBM at a young age, particularly under 50. Another indicator is the presence of multiple close relatives diagnosed with GBM or other related cancers, such as three or four glioma cases. The presence of a known cancer predisposition syndrome, like NF1 or Li-Fraumeni Syndrome, in the family is also a clear reason to seek counseling.
A genetic counselor will review the family’s medical history to create a detailed risk assessment and determine the likelihood of an inherited mutation. If the risk is high, they may recommend germline genetic testing to confirm a pathogenic variant. The results offer information for managing the affected individual’s risk, guiding screening for other cancers, and informing family members of their potential risk.