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

By M. Kool, J. Koster, J. Bunt, Nancy E. Hasselt, Arjan Lakeman, P. V. van Sluis, D. Troost, N. S. Meeteren, H. Caron, J. Cloos and 8 more. PLoS ONE, 2008

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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. Methods and Findings 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 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. 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.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/f74be6abf8f84a80c6b21b36e49255d213c808a9

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Citations in the corpus

Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations (2012, positive): “Recent molecular studies have revealed that medulloblastoma comprises at least four distinct sub-entities, which differ in terms of cell-of-origin, clinicopathologic features, anddiseaseoutcome (Cho et al., 2011; Gibson et al., 2010; Kool et al., 2008; Northcott et al., 2011b; Remke et al., 2011).”
TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal (2013, background): “OTX2 expression was >100-fold higher in medulloblastoma patients without TERT promoter mutations than in those patients with TERT promoter mutations (note the log scale in Fig.”
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma (2010, background): “More recently, two integrated genomic investigations have revealed distinct transcriptional subclasses of medulloblastoma that also harbour genomic alterations in oncogenic signalling pathway”
Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. (2011, background): “neuronal differentiation markers, photoreceptor transcriptional markers, or both.(3)”
Medulloblastoma comprises four distinct molecular variants. (2011, background): “Not surprisingly, monosomy 6 was found exclusively in WNT tumors,(4,12,16,26) and 9q loss was found only in SHH tumors.(16) Multiple novel regions of genomic aberration were identified in SHH tumors, including chromosome 9p gain (P .”
Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas (2012, methodology): “Several of the earlier profiling studies showed that there might even be five or six subgroups of medulloblastoma [1, 9, 25], with further subdivisions of Group 3 and Group 4.”