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Tumor Biology of Vestibular Schwannomas
Built from Haynes-Glasscock-Shambaugh Surgery of the Ear, Seventh Edition
What’s inside
12 sections · 157 slides
The tumour and its clinical setting
- Vestibular schwannoma: sites of origin
- Purpose of studying tumour biology
- Incidence of sporadic unilateral tumours
- Clinical consequences of tumour growth
- Three groups of vestibular schwannoma
- Nomenclature used for gene and disease
- Cross-species homology of the NF2 gene
NF2-related schwannomatosis
- NF2-related schwannomatosis: definition
- Non-vestibular manifestations of NF2
- Epidemiology and age of onset in NF2
- Distinguishing NF2 from neurofibromatosis type 1
- Wishart and Gardner phenotypes
- Mosaic NF2
- Transmission risk in mosaic disease
Cystic vestibular schwannomas
- Cystic vestibular schwannoma: features
- MRI appearances of cystic tumours
- Surgical and radiosurgical outcomes in cystic tumours
The NF2 gene and its pathogenic variants
- Localisation and cloning of the NF2 gene
- Tumours carrying NF2 pathogenic variants
- Categories of pathogenic variant
- Where pathogenic variants arise in a gene
- Variant spectrum: sporadic versus familial tumours
- The Ahronowitz variant database
- Variant distribution in meningiomas
- The CGA to TGA arginine transition
- Exons spared by pathogenic variants
- Genotype and phenotype severity
- Domain location and phenotype
- NF2 genetic severity score
- Clinical application of the severity score
- Revised severity scale from functional outcomes
- Outcomes predicted by NF2 class
- Intrafamilial variability of NF2
- Non-coding mechanisms of NF2 inactivation
Merlin: structure and tumour suppressor function
- Merlin: the NF2 gene product
- NF2 mRNA isoforms I and II
- Domain organisation of merlin
- Merlin and the ERM protein family
- Merlin and the actin cytoskeleton
- Subcellular distribution of merlin
- Evidence that merlin suppresses growth
- Heterozygous Nf2 knockout mouse phenotype
- Homozygous Nf2 loss and embryogenesis
- Conditional Nf2 knockout in Schwann cells
- Nf2 inactivation in arachnoidal cells
Merlin signalling and regulation
- Merlin's binding partners
- Major protein-protein interactions that modulate merlin’s growth regulatory function
- Major protein-protein interactions that modulate merlin’s growth regulatory function (continued)
- Major protein-protein interactions that modulate merlin’s growth regulatory function: mechanism
- Major protein-protein interactions that modulate merlin’s growth regulatory function: mechanism (continued)
- Major protein-protein interactions that modulate merlin’s growth regulatory function: mechanism (continued)
- Major protein-protein interactions that modulate merlin’s growth regulatory function: mechanism (continued)
- Intramolecular folding of merlin
- Open and closed conformations
- Merlin conformation as a growth switch
- Phosphorylation switch of merlin
- Merlin and CD44 as a molecular switch
- Cell density and merlin phosphorylation
- Rac1 and PAK-mediated inactivation of merlin
- PKA and AKT: degradation of merlin
- Pak1 regulation by merlin
- MYPT-1-PP1delta and CPI-17
- Conformational control in the ERM family
- HRS and hepatocyte growth factor signalling
- PI3K and AKT signalling in schwannoma
- PIKE-L and inhibition of PI3-kinase
- YAP1, LATS1/2 and B1-integrin
- Cadherins and contact inhibition
Promoter, splicing and gene expression
- The NF2 gene promoter
- NF2 promoter activity in embryogenesis
- Promoter activity in neural crest migration
- Alternatively spliced NF2 mRNA isoforms
Growth markers and expression profiling
- Ki-67 as a proliferation index
- PET imaging and metabolic activity
- TGF-beta1 and beta1-integrin immunostaining
- Proliferation indices across tumour types
- Cyclin D1 and cyclin D3 expression
- Limits of proliferation markers in VS
- cDNA microarray findings in schwannoma
- Next-generation sequencing of sporadic tumours
- A second sequencing cohort
- Osteonectin, endoglin and the pRB-CDK pathway
Environmental exposure and genetic screening
- Therapeutic radiation and tumour induction
- Risk of tumours induced by therapeutic radiation
- Radiation caution in tumour-prone conditions
- Cellular telephone use and schwannoma risk
- Conflicting mobile telephone evidence
- Indications for genetic and clinical screening
- Surveillance schedule for at-risk children
- Mutation screening in first-degree relatives
- Value of identifying the family variant
Targeted drug and gene therapy
- Strategies for molecular treatment
- Restoring merlin in animal models
- ErbB2 as a therapeutic target
- EGFR and ErbB2 inhibitors in NF2
- Rac inhibition in schwannoma cells
- PI3K/AKT activation in human schwannoma
- Screening PI3K/AKT inhibitors
- mTOR signalling and angiogenesis
- Alternative pathways downstream of merlin loss
- Everolimus trials in NF2
- Phase 0 presurgical everolimus study
- Adverse effects of everolimus
- Bevacizumab: mechanism and role
- Bevacizumab outcomes in NF2 cohorts
- Further bevacizumab evidence and adverse effects
- Viral vector gene delivery
- Non-viral delivery and surgical access
- Immunotherapy with VEGFR-specific vaccination
- Combined modality and radiosensitisation
- Schwannomatosis
Genetics of paragangliomas
- Hereditary paraganglioma syndromes
- SDH gene mutations in paraganglioma
- Function of the SDH complex
- PHD2 mutations and HIF regulation
Summary
- Core molecular sequence
- Key points to carry forward
- Direction of the field
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- Haynes-Glasscock-Shambaugh Surgery of the Ear, Seventh Edition
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