title: Rapid diagnosis of medulloblastoma molecular subgroups.
abstract: OBJECTIVE
  Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management.
  
  
  METHODS
  Minimal mRNA expression signatures diagnostic for the Wnt/Wingless (WNT) and Sonic Hedgehog (SHH) subgroups were developed, validated, and used to assign subgroup affiliation in 173 tumors from four independent cohorts, alongside a systematic investigation of subgroup clinical and molecular characteristics.
  
  
  RESULTS
  WNT tumors [12% (21/173)] were diagnosed >5 years of age (peak, 10 years), displayed classic histology, CTNNB1 mutation (19/20), and associated chromosome 6 loss, and have previously been associated with favorable prognosis. SHH cases [24% (42/173)] predominated in infants (<3 years) and showed an age-dependent relationship to desmoplastic/nodular pathology; all infant desmoplastic/nodular cases (previously associated with a good outcome) were SHH-positive, but these relationships broke down in noninfants. PTCH1 mutations were common [34% (11/32)], but PTCH1 exon1c hypermethylation, chromosome 9q and REN (KCTD11) genetic loss were not SHH associated, and SMO or SUFU mutation, PTCH1 exon1a or SUFU hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of COL1A2 methylation. WNT/SHH-independent medulloblastomas [64% (110/173)] showed all histologies, peaked at 3 and 6 years, and were exclusively associated with chromosome 17p loss.
  
  
  CONCLUSIONS
  Medulloblastoma subgroups are characterized by distinct genomic, epigenomic and clinicopathologic features, and clinical outcomes. Validated array-independent gene expression assays for the rapid assessment of subgroup affiliation in small biopsies provide a basis for their routine clinical application, in strategies including molecular disease-risk stratification and delivery of targeted therapeutics.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Schwalbe
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lindsey
authors.forename: Debbie
authors.initials: D
authors.lastname: Straughton
authors.forename: Twala L
authors.initials: TL
authors.lastname: Hogg
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.forename: Hisham
authors.initials: H
authors.lastname: Megahed
authors.forename: Sarra L
authors.initials: SL
authors.lastname: Ryan
authors.forename: Meryl E
authors.initials: ME
authors.lastname: Lusher
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D018287:Carcinoma, Large Cell / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D016022:Case-Control Studies; D002528:Cerebellar Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D016000:Cluster Analysis; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D018895:Microsatellite Repeats; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D051153:Wnt Proteins; D051176:beta Catenin