Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Abstract

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0958-8) contains supplementary material, which is available to authorized users.

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

“…Interestingly, loss of the 17p region is a rather common chromosomal aberration in different tumor types. In medulloblastomas, a malignancy arising from cerebellar cell precursors, loss of 17p is found in up to 50% of the tumors and is considered an indicator of a poor prognosis (48)(49)(50), and although 17p loss is more frequent in medulloblastoma groups 3 (ϳ45%) and 4 (ϳ60%), up to 20% of Shh group medulloblastomas present deletions in 17p (51), converting it into a common feature among different medulloblastoma types. However, the fact that tp53 gene is located in the 17p13.1 band led to the hypothesis that tumorigenicity associated with 17p loss was due mostly to a lack of p53 expression.…”

Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

“…18 SHH tumors are associated with desmoplastic histology in the vast majority of cases, in both infant (89%) and adult tumors (nearly all), but only 25% of cases in children. 19 As many as 84% of adult medulloblastoma tumors may show evidence of activation of the SHH pathway. 20 When considering both pediatric and adult cases, most studies report a prevalence of approximately 28%.…”

“…20 When considering both pediatric and adult cases, most studies report a prevalence of approximately 28%. 19 Notably, more than half of medulloblastoma cases are driven by the SHH pathway in the infant population as well as adults. 19 Interestingly, WNT pathway activation is less frequent in adult medulloblastomas.…”

“…19 Notably, more than half of medulloblastoma cases are driven by the SHH pathway in the infant population as well as adults. 19 Interestingly, WNT pathway activation is less frequent in adult medulloblastomas. 20 Further studies have substantiated these differences in pathway activation as compared to pediatric cases.…”

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

“…These data could also explain the higher proliferative capacity and growth advantages observed in UW402 when compared to UW473 cells. Moreover, we correlated the cytogenetic findings of both cell lines to chromosomal profiles described for each MB group of new molecular classification in the meta-analysis paper by Kool et al (2012). Interestingly, this classification system differentiates among two subgroups well characterized in their molecular pathways with few common chromosomal alterations (Group Wnt and Group Shh), and two subgroups molecularly less well characterized harboring a high number of chromosomal alterations (Group 3 and Group 4) .…”