Neuroblastoma Flashcards
What is an epigenetic marker seen in neuroblastoma?
- normal cells have hypermethylation of their NSD1 histone methyltransferase that causes the trimethylation of H4K20
- disruption of this process stops trimethylation of H4K20 and allows the MEISI oncogene to be overexpressed
What are some of the common sites of neuroblastoma and its metastasis?
- most common site is the adrenal glands but also common in the spinal cord of the neck and the pelvis
- commonly metastasises to the CNA, lungs and lymph nodes
Describe the incidence of neuroblastoma
- usually diagnosed by the age of 4
- one of the most common cancers of childhood
What is the usual outcome of neuroblastoma in children under 18 months?
- tumours are early stage
- spontaneous regression is possible
- responsive to treatment with >80% survival rates
Describe the usual outcome of neutroblastoma in children over 18 months
- tumours are late stage or metastatic
- require combined and invasive therapy
- > 40% survival rates
What are the cellular origins of neuroblastoma?
- neural crest cells
- stem cells derived from the sympathetic NS
- cells that migrate around the body to form neurons and supporting glial cells
What kinds of genetic features lead to favourable and aggressive neuroblastoma?
- triploid karyotypes are associated with better prognosis
- chromosomal losses at 1p and 11q and amplifications of MYCN are associated with worse prognosis
What are the 3 stages of neuroblastoma histology from benign to severe?
- ganlioneuroma - very few undifferentiated cells
- ganglioneuroblastoma - intermediate
- neuroblastoma - many undifferentiated cella
How can neuroblastoma be screened for?
- tumours can secrete catecholamines such as VMA to me measured in the urine but this only works for good prognosis tumours
- tumours take up lots of MBG so could use radiolabelled MBG to see where its taken up more by cells
How does spontanous regression occur in neuroblastoma?
- still poorly understood
- neurotrophin deprivation leads to apoptosis
- epigenetic changes involved
- immune mediated cell killing
- telomere shortening leads to apoptosis
What kind of germline mutations are seen in neuroblastoma?
- 1-2% of neuroblastomas are inherited in an autosomal dominant fashion
- 50% are in ALK
- others in PHOX2B tumour suppressor gene
What kind of somatic mutations are seen in neuroblastoma?
- 10% in ALK
- MYCN amplifications are associated with poor prognosis
What is ALK?
usually encodes a receptor tyrosine kinase but translocations can elad to an NPM-ALK fusion protein seen in neuroblasoma that activates the MAPK pathway
What is retinoic acid therapy in neuroblastoma?
- retinoic acid can induce differentiation bu reducing levels of MYCN and allowing cells to go down their normal differentiation pathways and apoptosose in time
- use in those with high risk MYCN+ tumours to counteract minimal residual disease
What are some amino acid changing mutations found in primary neuroblasoma?
- many neuroblastomas lack identifiable mutations and so mutations may be in copy number and epigenetic changes
- chromothripsis - shredding of chromosomes and genetic rearrangement
- mutations in chromatin remodelling genes like HDACs and HATs
- mutations in Rac/Rho components
- non-coding mutations in telomerase
Describe telomerase non-coding mutations seen in neuroblastoma
- recurrent genomic rearrangement at chromosome 5
- places telomerase reverse transcriptase next to strong enhancers
- leads to poor outcome tumours without MYCN amplification
Which gene mutations lead to high-risk neuroblastoma?
- MYCN
- hTERT
- ALK
- MYCN can upregulate hTERT and ALK
What does genome sequencing shoe about relapsed tumours in neuroblastoma?
- high rates of mutations
- due to treatment or disease progression
- very heterozygous
- RAS MAPK pathway often involved
Give 3 examples of epigenetic changes seen in neuroblastoma
- tumour suppressor hypermethylation
- DNA methylation at CpG islands is associated with poor prognosis
- some tumour suppressor genes are silenced by histone marks
What are some potential future therapies for neuroblastoma?
– chimeric angiten receptors against G2D found on the surface of neuroblastoma cells
- retionic acid
- MYCN regulators
- ALK or ras inhibitors
