What is the role of genetic predisposition in the development and management of meningiomas?

Genetic Predisposition in Meningioma Development and Management

Genetic mutations play a crucial role in both the development and management of meningiomas, with specific genetic alterations determining tumor behavior, recurrence risk, and optimal surveillance strategies. 1, 2

Key Genetic Syndromes Associated with Meningiomas

Neurofibromatosis Type 2 (NF2)

• Most common genetic syndrome associated with meningiomas 3
• Autosomal dominant condition caused by pathogenic variants in the NF2 gene on chromosome 22q 2
• Occurs in approximately 50% of NF2 patients, often with multiple tumors 3
• Diagnostic criteria include:
  • Bilateral vestibular schwannomas
  • Family history of NF2 plus unilateral vestibular schwannoma
  • Any two of: meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities 2

Other Genetic Syndromes

• SMARCE1 mutations: Associated with clear cell meningiomas with up to 60% recurrence rates and potential for CNS dissemination 2
• BAP1/PBRM1 mutations: Associated with rhabdoid and/or papillary features; over 80% of BAP1-mutant and nearly 90% of PBRM1-mutant meningiomas are WHO grades 2 and 3 1
• LZTR1 mutations: Associated with meningiomas in both brain and spine 2
• SUFU mutations: Identified in familial multiple meningioma cases, affecting the hedgehog signaling pathway 4

Molecular Classification of Meningiomas

NF2 vs. Non-NF2 Driven Meningiomas

• Meningiomas can be divided into:
  • NF2-driven: Harboring NF2 gene variants
  • TRAKLS: With TRAF7, AKT1, KLF4, and SMO alterations
  • Not otherwise classified (NOS) 1

Prognostic Implications of Genetic Alterations

• TRAKLS genotype: Highly associated with grade 1 meningiomas and improved progression-free survival compared to NF2-altered meningiomas 1
• KLF4 mutations: Associated with favorable outcomes regardless of TRAF7 status 1
• Isolated TRAF7 alterations: Higher risk of recurrence within 60 months 1
• AKT1, SMO, PIK3CA alterations: Enriched in skull base meningiomas, with SMO predominant in olfactory groove location 1

Clinical Implications for Management

Genetic Testing Recommendations

• Genetic evaluation is recommended for:
  • Young patients with meningiomas
  • Patients with multiple meningiomas
  • Patients with specific histological subtypes (clear cell, rhabdoid, or papillary features) 2

Surveillance Strategies Based on Genetic Profile

• SMARCE1 mutations: Yearly neurologic examination and MRI of brain and spine until age 30, then every 2-3 years 2
• LZTR1 mutations: Baseline MRI brain and spine at diagnosis, then every 2-3 years beginning at age 15-19 years 2
• NF2 patients: Complete brain and spine MRI with dedicated internal acoustic canal protocol to evaluate for concurrent vestibular schwannomas and additional meningiomas 2

Tumor Behavior and Treatment Considerations

• SMARCE1-mutant clear cell meningiomas: Demonstrate aggressive behavior with recurrence and occasional CSF seeding, designated as WHO grade 2 tumors 1
• BAP1 loss: Linked to shorter time to recurrence 1
• Multiple meningiomas: Associated with higher risk of recurrence and progression, requiring more intensive surveillance 2

Somatic vs. Germline Mutations

• Somatic NF2 inactivation: Principal driver of tumor initiation in sporadic meningiomas 5
• Epigenetic alterations: NF2 promoter methylation found in 26% of meningiomas, particularly grade I tumors 6
• Germline mutations: Found in familial cases and cancer predisposition syndromes, requiring genetic counseling and family screening 2

Clinical Management Algorithm

1. For all meningioma patients:

   • Complete baseline MRI of brain and spine to evaluate for multiple lesions
   • Consider genetic testing if:
     • Young age at diagnosis
     • Multiple meningiomas
     • Family history of meningiomas or related tumors
     • Specific histological subtypes (clear cell, rhabdoid, papillary)

2. If genetic syndrome identified:

   • Implement syndrome-specific surveillance protocols
   • Consider genetic counseling for family members
   • Anticipate potential for multiple tumors and higher recurrence risk

3. For treatment decisions:

   • Consider genetic profile in risk stratification
   • More aggressive follow-up for genetically high-risk tumors (SMARCE1, BAP1, PBRM1)
   • Recognize favorable prognosis of certain genetic subtypes (KLF4-mutant)

The integration of genetic information into meningioma management allows for personalized risk assessment, targeted surveillance, and potentially improved patient outcomes.