title: The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma.
abstract: BACKGROUND
  Paediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints.
  
  
  RESULTS
  We report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG - CSGALNACT2:RET and the complex fusion DHX57:TMEM178:MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG.
  
  
  CONCLUSIONS
  These data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.
authors.forename: Diana
authors.initials: D
authors.lastname: Carvalho
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Lynn
authors.initials: L
authors.lastname: Bjerke
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.forename: Celeste
authors.initials: C
authors.lastname: Lopes
authors.forename: Rui M
authors.initials: RM
authors.lastname: Reis
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. chris.jones@icr.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
mesh_terms: D000465:Algorithms; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005910:Glioma / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D017350:N-Acetylgalactosaminyltransferases; C472560:chondroitin sulfate N-acetylgalactosaminyltransferase-2