Medulloblastoma comprises four distinct molecular variants

Paul A. Northcott, Andrey Korshunov, Hendrik Witt, Thomas Hielscher, Charles G Eberhart, Stephen Mack, Eric Bouffet, Steven C. Clifford, Cynthia E. Hawkins, Pim French, James T. Rutka, Stefan Pfister, Michael D. Taylor

Research output: Contribution to journalArticle

Abstract

Purpose Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. Methods We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays. Results Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status. Conclusion Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.

Original languageEnglish (US)
Pages (from-to)1408-1414
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number11
DOIs
StatePublished - Apr 10 2011

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Medulloblastoma
Immunohistochemistry
Demography
DNA
Genomics
Computational Biology
Transcriptome
Formaldehyde
Genes
Disease-Free Survival
Histology
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Northcott, P. A., Korshunov, A., Witt, H., Hielscher, T., Eberhart, C. G., Mack, S., ... Taylor, M. D. (2011). Medulloblastoma comprises four distinct molecular variants. Journal of Clinical Oncology, 29(11), 1408-1414. https://doi.org/10.1200/JCO.2009.27.4324

Medulloblastoma comprises four distinct molecular variants. / Northcott, Paul A.; Korshunov, Andrey; Witt, Hendrik; Hielscher, Thomas; Eberhart, Charles G; Mack, Stephen; Bouffet, Eric; Clifford, Steven C.; Hawkins, Cynthia E.; French, Pim; Rutka, James T.; Pfister, Stefan; Taylor, Michael D.

In: Journal of Clinical Oncology, Vol. 29, No. 11, 10.04.2011, p. 1408-1414.

Research output: Contribution to journalArticle

Northcott, PA, Korshunov, A, Witt, H, Hielscher, T, Eberhart, CG, Mack, S, Bouffet, E, Clifford, SC, Hawkins, CE, French, P, Rutka, JT, Pfister, S & Taylor, MD 2011, 'Medulloblastoma comprises four distinct molecular variants', Journal of Clinical Oncology, vol. 29, no. 11, pp. 1408-1414. https://doi.org/10.1200/JCO.2009.27.4324
Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S et al. Medulloblastoma comprises four distinct molecular variants. Journal of Clinical Oncology. 2011 Apr 10;29(11):1408-1414. https://doi.org/10.1200/JCO.2009.27.4324
Northcott, Paul A. ; Korshunov, Andrey ; Witt, Hendrik ; Hielscher, Thomas ; Eberhart, Charles G ; Mack, Stephen ; Bouffet, Eric ; Clifford, Steven C. ; Hawkins, Cynthia E. ; French, Pim ; Rutka, James T. ; Pfister, Stefan ; Taylor, Michael D. / Medulloblastoma comprises four distinct molecular variants. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 11. pp. 1408-1414.
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abstract = "Purpose Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. Methods We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays. Results Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98{\%} of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status. Conclusion Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.",
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AU - Mack, Stephen

AU - Bouffet, Eric

AU - Clifford, Steven C.

AU - Hawkins, Cynthia E.

AU - French, Pim

AU - Rutka, James T.

AU - Pfister, Stefan

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N2 - Purpose Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. Methods We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays. Results Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status. Conclusion Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.

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