Is glioblastoma multiforme (GBM) genetic?

Glioblastoma Multiforme Has Significant Genetic Components

Yes, glioblastoma multiforme (GBM) has significant genetic components, with both somatic mutations driving tumor development and rare hereditary factors that can predispose individuals to this cancer.

Genetic Alterations in GBM

GBM demonstrates complex genetic alterations that contribute to its development, progression, and treatment resistance:

Key Molecular Markers

• IDH1/2 mutations: Present in 5-10% of GBMs (primarily secondary GBMs) and associated with a more protracted disease course 1
• MGMT promoter methylation: Found in approximately 35% of GBMs and predicts benefit from alkylating chemotherapy 1
• EGFR alterations: Overexpression and EGFRvIII mutations are characteristic of GBMs and associated with poorer prognosis 1
• ATRX mutations: Specific for astrocytic lineage tumors 1
• BRAF mutations: Present in 3-5% of GBMs 1

Classification Based on Genetic Profile

GBMs can be classified into two main subtypes based on their genetic profiles:

1. Primary GBMs (90-95% of cases):

   • Develop de novo without evidence of progression from lower-grade tumors
   • Typically affect older adults
   • Characterized by EGFR amplification/mutation, PTEN mutations, and chromosome 10 loss

2. Secondary GBMs (5-10% of cases):

   • Develop from lower-grade gliomas
   • More common in younger patients
   • Higher frequency of IDH1/2 mutations (50-70%) and TP53 mutations (65%) 2
   • Higher rates of MGMT promoter methylation (75%) 2

Hereditary Factors in GBM

While most GBMs occur sporadically, there are several genetic syndromes and familial patterns associated with increased risk:

Known Cancer Predisposition Syndromes

• Li-Fraumeni Syndrome: Caused by germline TP53 mutations, with increased risk of various cancers including GBM 1
• Biallelic Mismatch Repair Deficiency (BMMRD): Caused by mutations in DNA mismatch repair genes, associated with brain tumors including GBM 1
• Neurofibromatosis: Particularly NF1, can predispose to various brain tumors including GBM

Rare Familial GBM Cases

Several studies have identified specific genetic mutations in rare families with multiple GBM cases:

• SMARCB1 gene mutations have been associated with earlier onset of GBM in affected families 3
• Exome sequencing of affected families has revealed variants in genes such as ERBB2, PMS2, and CHI3L1, as well as previously unrecognized genes 4
• Clustering of multiple variants in single genes (e.g., PTPRB, CROCC) and aggregation of affected genes in specific molecular pathways have been observed in familial cases 4

Clinical Implications of Genetic Findings

The genetic profile of GBM has important implications for:

1. Diagnosis and Classification: Molecular markers are now integral to GBM diagnosis and classification 1

2. Prognosis: Certain genetic alterations (e.g., IDH mutations) are associated with better prognosis 1

3. Treatment Selection:

   • MGMT promoter methylation predicts benefit from temozolomide chemotherapy 1
   • Targeted therapies based on specific genetic alterations are under investigation 5

4. Genetic Counseling: For patients with suspected hereditary syndromes or familial clustering 1

Future Directions

The genetic understanding of GBM continues to evolve:

• Development of targeted therapies against specific genetic alterations
• Improved molecular classification systems
• Better understanding of treatment resistance mechanisms
• Potential for early detection in high-risk individuals

Conclusion

GBM has a complex genetic landscape with both somatic mutations driving tumor development and rare hereditary factors. Understanding these genetic components is crucial for diagnosis, prognosis, and development of more effective treatments for this aggressive brain tumor.