Neuroblastoma Flashcards

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1
Q

What is an epigenetic marker seen in neuroblastoma?

A
  • 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
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2
Q

What are some of the common sites of neuroblastoma and its metastasis?

A
  • 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
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3
Q

Describe the incidence of neuroblastoma

A
  • usually diagnosed by the age of 4
  • one of the most common cancers of childhood
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4
Q

What is the usual outcome of neuroblastoma in children under 18 months?

A
  • tumours are early stage
  • spontaneous regression is possible
  • responsive to treatment with >80% survival rates
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5
Q

Describe the usual outcome of neutroblastoma in children over 18 months

A
  • tumours are late stage or metastatic
  • require combined and invasive therapy
  • > 40% survival rates
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6
Q

What are the cellular origins of neuroblastoma?

A
  • neural crest cells
  • stem cells derived from the sympathetic NS
  • cells that migrate around the body to form neurons and supporting glial cells
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7
Q

What kinds of genetic features lead to favourable and aggressive neuroblastoma?

A
  • triploid karyotypes are associated with better prognosis
  • chromosomal losses at 1p and 11q and amplifications of MYCN are associated with worse prognosis
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8
Q

What are the 3 stages of neuroblastoma histology from benign to severe?

A
  • ganlioneuroma - very few undifferentiated cells
  • ganglioneuroblastoma - intermediate
  • neuroblastoma - many undifferentiated cella
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9
Q

How can neuroblastoma be screened for?

A
  • 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
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10
Q

How does spontanous regression occur in neuroblastoma?

A
  • still poorly understood
  • neurotrophin deprivation leads to apoptosis
  • epigenetic changes involved
  • immune mediated cell killing
  • telomere shortening leads to apoptosis
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11
Q

What kind of germline mutations are seen in neuroblastoma?

A
  • 1-2% of neuroblastomas are inherited in an autosomal dominant fashion
  • 50% are in ALK
  • others in PHOX2B tumour suppressor gene
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12
Q

What kind of somatic mutations are seen in neuroblastoma?

A
  • 10% in ALK
  • MYCN amplifications are associated with poor prognosis
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13
Q

What is ALK?

A

usually encodes a receptor tyrosine kinase but translocations can elad to an NPM-ALK fusion protein seen in neuroblasoma that activates the MAPK pathway

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14
Q

What is retinoic acid therapy in neuroblastoma?

A
  • 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
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15
Q

What are some amino acid changing mutations found in primary neuroblasoma?

A
  • 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
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16
Q

Describe telomerase non-coding mutations seen in neuroblastoma

A
  • recurrent genomic rearrangement at chromosome 5
  • places telomerase reverse transcriptase next to strong enhancers
  • leads to poor outcome tumours without MYCN amplification
17
Q

Which gene mutations lead to high-risk neuroblastoma?

A
  • MYCN
  • hTERT
  • ALK
  • MYCN can upregulate hTERT and ALK
18
Q

What does genome sequencing shoe about relapsed tumours in neuroblastoma?

A
  • high rates of mutations
  • due to treatment or disease progression
  • very heterozygous
  • RAS MAPK pathway often involved
19
Q

Give 3 examples of epigenetic changes seen in neuroblastoma

A
  • tumour suppressor hypermethylation
  • DNA methylation at CpG islands is associated with poor prognosis
  • some tumour suppressor genes are silenced by histone marks
20
Q

What are some potential future therapies for neuroblastoma?

A

– chimeric angiten receptors against G2D found on the surface of neuroblastoma cells
- retionic acid
- MYCN regulators
- ALK or ras inhibitors