Article

Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.

Children's Hospital Boston, Boston, MA 02115, USA.
Journal of Clinical Oncology (impact factor: 18.37). 12/2010; 29(11):1424-30. DOI:10.1200/JCO.2010.28.5148 pp.1424-30
Source: PubMed

ABSTRACT Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.
We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.
Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.
Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.

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30 Aug 2012

Keywords

194 medulloblastomas
 
c-MYC copy number gains
 
children
 
common malignant brain tumor
 
complex genomic heterogeneity
 
DNA copy number
 
effective therapeutic strategies
 
event-free
 
globally influence mRNA
 
high-density single nucleotide polymorphism array
 
independent medulloblastoma data sets
 
lower rates
 
medulloblastomas
 
mRNA expression data
 
mRNA transcriptome
 
Non-negative matrix factorization-based clustering
 
poor clinical outcome
 
results detail
 
risk factors
 
unrecognized molecular subgroup