Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features

Kool, Marcel, Koster, Jan, Bunt, Jens, Hasselt, Nancy E., Lakeman, Arjan, van Sluis, Peter, Troost, Dirk, Schouten-van Meeteren, Netteke, Caron, Huib N., Cloos, Jacqueline, Mrsic, Alan, Ylstra, Bauke, Grajkowska, Wieslawa, Hartmann, Wolfgang, Pietsch, Torsten, Ellison, David, Clifford, Steven C. and Versteeg, Rogier (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PloS One, 3 8: e3088.1-e3088.14. doi:10.1371/journal.pone.0003088

Author Kool, Marcel
Koster, Jan
Bunt, Jens
Hasselt, Nancy E.
Lakeman, Arjan
van Sluis, Peter
Troost, Dirk
Schouten-van Meeteren, Netteke
Caron, Huib N.
Cloos, Jacqueline
Mrsic, Alan
Ylstra, Bauke
Grajkowska, Wieslawa
Hartmann, Wolfgang
Pietsch, Torsten
Ellison, David
Clifford, Steven C.
Versteeg, Rogier
Title Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2008-08-28
Year available 2008
Sub-type Article (original research)
DOI 10.1371/journal.pone.0003088
Open Access Status DOI
Volume 3
Issue 8
Start page e3088.1
End page e3088.14
Total pages 14
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
Subject 1100 Agricultural and Biological Sciences
1300 Biochemistry, Genetics and Molecular Biology
2700 Medicine
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. 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID UVA-2001-2558
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 372 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 23 Feb 2014, 23:17:00 EST by Jens Bunt on behalf of Queensland Brain Institute