title: Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.
abstract: BACKGROUND
  Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms.
  
  
  RESULTS
  To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas.
  
  
  CONCLUSIONS
  The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.
authors.affiliation: Department of Human Genetics, Academic Medical Center, Amsterdam, the Netherlands. m.kool@amc.uva.nl
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Jens
authors.initials: J
authors.lastname: Bunt
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Hasselt
authors.forename: Arjan
authors.initials: A
authors.lastname: Lakeman
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Netteke Schouten-van
authors.initials: NS
authors.lastname: Meeteren
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Alan
authors.initials: A
authors.lastname: Mrsić
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg