Genetics of Glioblastoma
Glioblastoma (GBM) is a complex and heterogeneous disease, and genetics play a crucial role in its development and progression. Here are some key genetic alterations and mutations associated with GBM:
Core Pathways Altered in Glioblastoma
1. TP53 pathway: Mutations in TP53 (30-40%) or its regulators (e.g., MDM2, MDM4) disrupt the p53 tumor suppressor pathway.
2. RB pathway: Alterations in RB1 (10-20%) or its regulators (e.g., CDK4, CDKN2A) disrupt the retinoblastoma tumor suppressor pathway.
3. PI3K/AKT pathway: Mutations or amplifications in PIK3CA (10-20%), PIK3R1, or AKT1/2/3 activate the PI3K/AKT signaling pathway.
4. MAPK pathway: Mutations or amplifications in BRAF (5-10%), KRAS, or NF1 activate the MAPK signaling pathway.
Frequently Mutated Genes in Glioblastoma
1. IDH1/2 (5-10%): Mutations in IDH1 or IDH2 are associated with a better prognosis and are more common in secondary GBM.
2. ATRX (10-20%): Mutations in ATRX are associated with alternative lengthening of telomeres (ALT) and are more common in secondary GBM.
3. TERT (20-30%): Mutations in TERT are associated with increased telomerase activity and are more common in primary GBM.
Amplifications and Deletions in Glioblastoma
1. EGFR amplification (40-50%): Amplification of EGFR is associated with a worse prognosis.
2. CDKN2A deletion (30-40%): Deletion of CDKN2A is associated with a worse prognosis.
3. PTEN deletion (10-20%): Deletion of PTEN is associated with a worse prognosis.
Molecular Subtypes of Glioblastoma
1. Proneural: Characterized by mutations in IDH1/2 and ATRX.
2. Classical: Characterized by amplification of EGFR and deletion of CDKN2A.
3. Mesenchymal: Characterized by mutations in NF1 and PTEN.
Understanding the genetic landscape of glioblastoma is crucial for developing effective therapeutic strategies and improving patient outcomes.
