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

Yoon Jae Cho, Aviad Tsherniak, Pablo Tamayo, Sandro Santagata, Azra Ligon, Heidi Greulich, Rameen Berhoukim, Vladimir Amani, Liliana Goumnerova, Charles G Eberhart, Ching C. Lau, James M. Olson, Richard J. Gilbertson, Amar Gajjar, Olivier Delattre, Marcel Kool, Keith Ligon, Matthew Meyerson, Jill P. Mesirov, Scott L. Pomeroy

Research output: Contribution to journalArticle

Abstract

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. Wereveal 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-183̃96̃182 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.

Original languageEnglish (US)
Pages (from-to)1424-1430
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number11
DOIs
StatePublished - Apr 10 2011

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Medulloblastoma
MicroRNAs
Messenger RNA
Transcriptome
Brain Neoplasms
Chromosome Aberrations
Disease-Free Survival
Single Nucleotide Polymorphism
Cluster Analysis
Neoplasms
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cho, Y. J., Tsherniak, A., Tamayo, P., Santagata, S., Ligon, A., Greulich, H., ... Pomeroy, S. L. (2011). Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. Journal of Clinical Oncology, 29(11), 1424-1430. https://doi.org/10.1200/JCO.2010.28.5148

Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. / Cho, Yoon Jae; Tsherniak, Aviad; Tamayo, Pablo; Santagata, Sandro; Ligon, Azra; Greulich, Heidi; Berhoukim, Rameen; Amani, Vladimir; Goumnerova, Liliana; Eberhart, Charles G; Lau, Ching C.; Olson, James M.; Gilbertson, Richard J.; Gajjar, Amar; Delattre, Olivier; Kool, Marcel; Ligon, Keith; Meyerson, Matthew; Mesirov, Jill P.; Pomeroy, Scott L.

In: Journal of Clinical Oncology, Vol. 29, No. 11, 10.04.2011, p. 1424-1430.

Research output: Contribution to journalArticle

Cho, YJ, 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 2011, 'Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome', Journal of Clinical Oncology, vol. 29, no. 11, pp. 1424-1430. https://doi.org/10.1200/JCO.2010.28.5148
Cho, Yoon Jae ; Tsherniak, Aviad ; Tamayo, Pablo ; Santagata, Sandro ; Ligon, Azra ; Greulich, Heidi ; Berhoukim, Rameen ; Amani, Vladimir ; Goumnerova, Liliana ; Eberhart, Charles G ; Lau, Ching C. ; Olson, James M. ; Gilbertson, Richard J. ; Gajjar, Amar ; Delattre, Olivier ; Kool, Marcel ; Ligon, Keith ; Meyerson, Matthew ; Mesirov, Jill P. ; Pomeroy, Scott L. / Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 11. pp. 1424-1430.
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abstract = "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. Wereveal 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-183̃96̃182 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.",
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T1 - Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome

AU - Cho, Yoon Jae

AU - Tsherniak, Aviad

AU - Tamayo, Pablo

AU - Santagata, Sandro

AU - Ligon, Azra

AU - Greulich, Heidi

AU - Berhoukim, Rameen

AU - Amani, Vladimir

AU - Goumnerova, Liliana

AU - Eberhart, Charles G

AU - Lau, Ching C.

AU - Olson, James M.

AU - Gilbertson, Richard J.

AU - Gajjar, Amar

AU - Delattre, Olivier

AU - Kool, Marcel

AU - Ligon, Keith

AU - Meyerson, Matthew

AU - Mesirov, Jill P.

AU - Pomeroy, Scott L.

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Y1 - 2011/4/10

N2 - 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. Wereveal 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-183̃96̃182 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.

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