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SUMMARY:Online seminar: ‘Structural variation in anaplastic astrocytoma 
 highlights therapeutic opportunities’ - Prof Nathan Harmston\, Assistant
  Professor\, Yale-NUS/Duke-NUS\, Singapore
DTSTART:20211209T113000Z
DTEND:20211209T123000Z
UID:TALK166690@talks.cam.ac.uk
CONTACT:Alison Quenault
DESCRIPTION:Anaplastic Astrocytoma (AA) is a diffusely infiltrating\, mali
 gnant\, primary brain tumour (typically classified as a Grade III glioma)\
 , which can occur de novo or progress from grade II astrocytomas. Despite 
 numerous studies on the mutational landscape of astrocytomas\, our underst
 anding of the molecular mechanisms involved in the formation and progressi
 on of these tumours is far from complete. Here\, we use whole genome seque
 ncing to investigate eight anaplastic AA tumours samples\, which exhibited
  both Grade II and Grade III pathology. In this study\, we focused on the 
 mutational and structural variant landscape of the Grade III component. Ou
 r analysis revealed widespread heterogeneity in the location\, size and nu
 mber of structural variants in Grade III AA tumours. Of the samples analys
 ed\, two showed a whole-genome doubling event and we further observed mass
 ive\, clustered genomic rearrangements in another two samples\, indicative
  of chromothripsis. We hypothesised that drastic\, large-scale changes to 
 cellular karyotype could result in selective vulnerabilities in AA. Studie
 s in yeast have shown that increased transcription and translation resulti
 ng from hyperploidy increases accumulation of misfolded proteins and depen
 dence on the proteasomal machinery. We find that treatment of hyperploid g
 rade IV astrocytoma cell-lines with proteasome inhibitors resulted in incr
 eased cytotoxicity (as measured by LDH activity) compared to near-euploid 
 astrocytoma cells. This suggests the potential for hyperploidy to be used 
 as a selective or correlative biomarker for proteasome inhibition therapy 
 in anaplastic astrocytoma.
LOCATION:Virtual Seminar 
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