Journal Article

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

van Sluis, Peter, Versteeg, Rogier, Ellison, David, Lakeman, Arjan, Grajkowska, Wieslawa, Hasselt, Nancy E., Bunt, Jens, Koster, Jan, Troost, Dirk, Meeteren, Netteke Schouten-van, Cloos, Jacqueline, Mršić, Alan, Ylstra, Bauke, Clifford, Steven C., Kool, Marcel, Caron, Huib N., Hartmann, Wolfgang, Pietsch, Torsten

2008

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Adolescent / Adult / Algorithms / Analysis / Antigens / Brain / Brain cancer / Brain research / Brain tumors / Cancer metastasis / Cancer therapies / Care and treatment / Cell Biology/Gene Expression / Cerebellar Neoplasms - classification / Cerebellar Neoplasms - genetics / Cerebellar Neoplasms - pathology / Child / Child, Preschool / Children / Chromosome 17 / Chromosome 6 / Chromosome aberrations / Chromosomes / Classification / Clinical trials / Computational Biology/Genomics / Computational Biology/Molecular Genetics / Copy number / Cytogenetics / Deoxyribonucleic acid / Diagnosis / DNA / DNA Mutational Analysis / DNA, Neoplasm - genetics / Female / Gene expression / Gene Expression Profiling / Genes / Genetic research / Genetics / Genetics and Genomics/Bioinformatics / Genetics and Genomics/Cancer Genetics / Genetics and Genomics/Gene Expression / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Genomics / Genomics / Histology / Humans / Hybridization / Integrated approach / Male / Medical diagnosis / Medical research / Medulloblastoma / Medulloblastoma - classification / Medulloblastoma - genetics / Medulloblastoma - pathology / Metastases / Metastasis / Molecular biology / Monosomy / Mutation / Neuropathology / Nucleic Acid Hybridization / Oncology / Oncology/Neuro-Oncology / Oncology/Pediatric Oncology / Pathogenesis / Pathology / Patients / Pediatrics / Pediatrics and Child Health/Pediatric Oncology / Prognosis / Quality of life / RNA / RNA, Neoplasm - genetics / Rodents / Side effects / Signal Transduction / Studies / Transforming Growth Factor beta - physiology / Transgenic animals / Tumors / Wnt protein / β-Catenin