Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

Abstract

BackgroundMedulloblastoma 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.Methods and FindingsTo 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 β-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.ConclusionsThe 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.

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

“…Functional genomic platforms have reproducibly shown that medulloblastoma can be categorized into four molecular subclasses that are distinct in terms of both prognosis and predicted therapeutic responses (Pomeroy et al, 2002;Thompson et al, 2006;Kool et al, 2008;Northcott et al, 2010). Medulloblastoma subtypes A and B are characterized by exclusive aberrant activation of the Wnt and Shh signaling pathways, respectively.…”

“…Given current efforts toward the molecular characterization of medulloblastomas into distinct subtypes (Pomeroy et al, 2002;Thompson et al, 2006;Kool et al, 2008;Northcott et al, 2010), we were interested to see if Bmi1 is implicated in any particular molecular subgroup of medulloblastomas. Although Bmi1 expression is elevated across all medulloblastoma molecular subtypes, its levels are highest in the most aggressive subtypes of medulloblastoma, groups C and D. These subtypes are associated with poor survival and invasive metastatic disease, and they remain refractory to current treatment modalities.…”

“…Despite current multimodality treatment of surgical resection, radiation and chemotherapy, jointly yielding an 80% 5-year survival rate, there remains significant treatment-induced morbidity and long-term clinical sequelae (Gilbertson, 2004;Huse and Holland, 2010). Recent molecular classification of medulloblastoma has not only reconceptualized the heterogeneity that exists within pathological subtypes, but has given context to the role of key developmental signaling pathways in the pathogenesis of this tumor (Pomeroy et al, 2002;Thompson et al, 2006;Kool et al, 2008;Northcott et al, 2010).…”

Embryonal neural tumours and cell death

“…Gain of chromosome 1q is a negative prognostic marker for survival also in medulloblastoma [57], but so far no correlation to the expression of Mcl-1 has been reported. Survivin is encoded by a single-copy gene located on human chromosome 17q25, a region that is frequently gained in unfavourable medulloblastoma and highrisk neuroblastoma [58][59][60]. Moreover, elevated expression of survivin is highly correlated to poor survival in both medulloblastoma and neuroblastoma (Fig.…”

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

“…Recently, molecular studies have demonstrated that MB is not a single disease, but comprises a collection of four distinct molecular subgroups (Cho et al 2011;Kool et al 2008;Northcott et al 2011;Remke et al 2011a, b;Thompson et al 2006). Two of these subgroups are characterized by either activated WNT or SHH signaling, consistently show the most distinct genetic profiles, and remain Non-WNT/Non-SHH tumors named Group 3 and Group 4.…”