title: FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma.
abstract: OBJECTIVE
  Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors.
  
  
  METHODS
  We combined transcriptome and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were used to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. The prognostic power of follistatin-like 5 (FSTL5) immunopositivity was tested for 235 nonoverlapping medulloblastoma samples on two independent tissue microarrays.
  
  
  RESULTS
  Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. Stable subgroup separation was achieved by using the 300 transcripts that varied the most. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time polymerase chain reaction. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, more than 50% of non-WNT/non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with a good prognosis who would otherwise be considered intermediate or high-risk on the basis of current molecular subgrouping.
  
  
  CONCLUSIONS
  FSTL5 expression denoted a dismal prognosis both within and across medulloblastoma subgroups. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes constitutes a reliable and cost-effective tool for prognostication in future clinical trials of medulloblastoma.
authors.affiliation: German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bender
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Huriye
authors.initials: H
authors.lastname: Cin
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Daniel
authors.initials: D
authors.lastname: Haag
authors.forename: Grischa
authors.initials: G
authors.lastname: Toedt
authors.forename: Andrea
authors.initials: A
authors.lastname: Wittmann
authors.forename: Anna
authors.initials: A
authors.lastname: Schöttler
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.forename: Wolfram
authors.initials: W
authors.lastname: Scheurlen
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D015331:Cohort Studies; D018572:Disease-Free Survival; D038702:Follistatin-Related Proteins / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D046228:Microarray Analysis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C569961:FSTL5 protein, human; D038702:Follistatin-Related Proteins