|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Cho, Y-J, Tsherniak, A, Tamayo, P, Santagata, S, Ligon, A, Greulich, H, Berhoukim, R, Amani, V, Goumnerova, L, Eberhart, CG, Lau, CC, Olson, JM, Gilbertson, RJ, Gajjar, A, Delattre, O, Kool, M, Ligon, K, Meyerson, M, Mesirov, JP, Pomeroy, SL|
|Journal||J Clin Oncol|
|Date Published||2011 Apr 10|
|Keywords||Algorithms, Cerebellar Neoplasms, Child, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Genomics, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Medulloblastoma, Polymorphism, Single Nucleotide, Predictive Value of Tests, Prognosis, RNA, Neoplasm, Transcription Factors|
PURPOSE: 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.
PATIENTS AND METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
|Alternate Journal||J. Clin. Oncol.|
|PubMed Central ID||PMC3082983|
|Grant List||R01-109467 / / PHS HHS / United States |
R01 GM074024 / GM / NIGMS NIH HHS / United States
6R01-CA-121941-04 / CA / NCI NIH HHS / United States
R01 CA129541-04 / CA / NCI NIH HHS / United States
R01 CA129541 / CA / NCI NIH HHS / United States
R01-GM074024 / GM / NIGMS NIH HHS / United States
R01 NS055089 / NS / NINDS NIH HHS / United States
R33-CA97556-01 / CA / NCI NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
R01-NS055089 / NS / NINDS NIH HHS / United States
P50-CA112962 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States
R33 CA097556 / CA / NCI NIH HHS / United States