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Intertumoral Heterogeneity within Medulloblastoma Subgroups
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SUMMARY While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
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“SHH-MB is the most genetically understood further classified in four molecular subtypes (SHH-MB alpha, beta, gamma, delta) [3]”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [3]
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Metadata
- Authors
- Cavalli, F. M. G., Remke, M., Rampasek, L., Peacock, J., Shih, D. J. H., Luu, B., Garzia, L., Torchia, J., Nor, C., Morrissy, A. S., Agnihotri, S., Thompson, Y. Y., Kuzan-Fischer, C. M., Farooq, H., Isaev, K., Daniels, C., Cho, B.-K., Kim, S.-K., Wang, K.-C., Lee, J. Y., Grajkowska, W. A., Perek-Polnik, M., Vasiljevic, A., Faure-Conter, C., Jouvet, A., Giannini, C., Nageswara Rao, A. A., Li, K. K. W., Ng, H.-K., Eberhart, C. G., Pollack, I. F., Hamilton, R. L., Gillespie, G. Y., Olson, J. M., Leary, S., Weiss, W. A., Lach, B., Chambless, L. B., Thompson, R. C., Cooper, M. K., Vibhakar, R., Hauser, P., van Veelen, M.-L. C., Kros, J. M., French, P. J., Ra, Y. S., Kumabe, T., López-Aguilar, E., Zitterbart, K., Sterba, J., Finocchiaro, G., Massimino, M., Van Meir, E. G., Osuka, S., Shofuda, T., Klekner, A., Zollo, M., Leonard, J. R., Rubin, J. B., Jabado, N., Albrecht, S., Mora, J., Van Meter, T. E., Jung, S., Moore, A. S., Hallahan, A. R., Chan, J. A., Tirapelli, D. P. C., Carlotti, C. G., Fouladi, M., Pimentel, J., Faria, C. C., Saad, A. G., Massimi, L., Liau, L. M., Wheeler, H., Nakamura, H., Elbabaa, S. K., Perezpeña-Diazconti, M., Chico Ponce de León, F., Robinson, S., Zapotocky, M., Lassaletta, A., Huang, A., Hawkins, C. E., Tabori, U., Bouffet, E., Bartels, U., Dirks, P. B., Rutka, J. T., Bader, G. D., Reimand, J., Goldenberg, A., Ramaswamy, V., & Taylor, M. D.
- Affiliations
- Hospital for Sick Children (CA)
- German Cancer Research Center (DE)
- University of Toronto (CA)
- University of Pittsburgh (US)
- Ontario Institute for Cancer Research (CA)
- Seoul National University (KR)
- Centre de Recherche en Neurosciences de Lyon (FR)
- Université de Lyon (FR)
- Mayo Clinic (US)
- Chinese University of Hong Kong (HK)
- Johns Hopkins University (US)
- University of Alabama at Birmingham (US)
- Seattle Children's Hospital (US)
- University of California, San Francisco (US)
- Vanderbilt University Medical Center (US)
- University of Colorado Denver (US)
- Erasmus MC (NL)
- Kitasato University (JP)
- Masaryk University (CZ)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Emory University (US)
- Osaka National Hospital (JP)
- University of Naples Federico II (IT)
- St. Louis Children's Hospital (US)
- McGill University (CA)
- Montreal Children's Hospital (CA)
- Hospital Sant Joan de Déu Barcelona (ES)
- Chonnam National University (KR)
- The University of Queensland (AU)
- University of Calgary (CA)
- Universidade de São Paulo (BR)
- Cincinnati Children's Hospital Medical Center (US)
- Centro Hospitalar Lisboa Norte (PT)
- University of Arkansas for Medical Sciences (US)
- Università Cattolica del Sacro Cuore (IT)
- University of California, Los Angeles (US)
- The University of Sydney (AU)
- Kumamoto University (JP)
- Saint Louis University (US)
- Rainbow Babies & Children's Hospital (US)
- Mount Sinai Hospital (CA)
- Corresponding author
- Goldenberg, Anna
- Ramaswamy, Vijay
- Taylor, Michael D.
- ORCID
- Cavalli, Florence M.G.
- Remke, Marc
- Shih, David J.H.
- Garzia, Livia
- Morrissy, A. Sorana
- Agnihotri, Sameer
- Kuzan-Fischer, Claudia M.
- Farooq, Hamza
- Isaev, Keren
- Kim, Seung-Ki
- Wang, Kyu-Chang
- Lee, Ji Yeoun
- Vasiljevic, Alexandre
- Giannini, Caterina
- Li, Kay Ka Wai
- Ng, Ho-Keung
- Eberhart, Charles G.
- Pollack, Ian F.
- Hamilton, Ronald L.
- Gillespie, G. Yancey
- Olson, James M.
- Leary, Sarah
- Weiss, William A.
- Chambless, Lola B.
- Vibhakar, Rajeev
- Kros, Johan M.
- French, Pim J.
- Kumabe, Toshihiro
- Finocchiaro, Gaetano
- Massimino, Maura
- Shofuda, Tomoko
- Zollo, Massimo
- Rubin, Joshua B.
- Jabado, Nada
- Albrecht, Steffen
- Mora, Jaume
- Jung, Shin
- Moore, Andrew S.
- Chan, Jennifer A.
- Carlotti, Carlos G.
- Fouladi, Maryam
- Pimentel, José
- Saad, Ali G.
- Massimi, Luca
- Liau, Linda M.
- Wheeler, Helen
- Nakamura, Hideo
- Elbabaa, Samer K.
- Robinson, Shenandoah
- Huang, Annie
- Hawkins, Cynthia E.
- Tabori, Uri
- Bartels, Ute
- Dirks, Peter B.
- Rutka, James T.
- Bader, Gary D.
- Reimand, Jüri
- Goldenberg, Anna
- Ramaswamy, Vijay
- Taylor, Michael D.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 31
- Issue
- 6
- Pages
- 737-754.e6
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6163053
- OpenAlex
- W2626440326
- Semantic Scholar
- f47b26a564646a2fc0484d60010014706628a8aa
- Cited by
- 1,219
- References
- 47
- Citations by year
- 2026: 97 · 2025: 150 · 2024: 119 · 2023: 149 · 2022: 146 · 2021: 168 · 2020: 147 · 2019: 108 · 2018: 103 · 2017: 24
- FWCI
- 59.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- dx.doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- Garron Family Chair in Childhood Cancer Research
- The University of Toronto
- NIH (R01CA159859, R01CA148699, R01 NS084063)
- Terry Fox Research Institute
- Brain Tumor Foundation of Canada
- McLaughlin Center
- Worldwide Cancer Research
- Canadian Institutes of Health Research
- Pediatric Brain Tumor Foundation
- St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)
- Alex's Lemonade Stand Young Investigator Award
- Garron Family Cancer Center Pitblado Discovery
- Collaborative Ependymoma Research Network
- Swifty Foundation
- Mildred Scheel Cancer Foundation
- NSERC Discovery Grant (RGPIN-2016-06485)
- Cancer Research Society (21089)
- Hungarian Brain Research Program (KTIA_13_NAP-A-V/3)
- TÁMOP (4.2.2.A-11/1/KONV-2012-0025)
- Hungarian Academy of Sciences
- OPVK (CZ.1.07/2.3.00/20.0183)
- Baldrick's Foundation
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
- Keywords
- medulloblastoma, tumor heterogeneity, molecular subtypes, similarity network fusion, DNA methylation, gene expression, somatic copy number alterations, sonic hedgehog medulloblastoma, integrative clustering, patient stratification, clinical trial stratification
- MeSH terms
- Humans, Medulloblastoma, Cohort Studies, Cluster Analysis, DNA Methylation, Gene Expression Profiling, Genomics, DNA Copy Number Variations, Precision Medicine
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