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.

2nd Department of Pediatrics Semmelweis University Budapest 1094 Hungary

Centre de Pathologie EST Groupement Hospitalier EST Université de Lyon Bron 69677 France

Centre de Pathologie et Neuropathologie Est Centre de Biologie et Pathologie Est Groupement Hospitalier Est Hospices Civils de Lyon Bron 69677 France; ONCOFLAM Neuro Oncologie et Neuro Inflammation Centre de Recherche en Neurosciences de Lyon Lyon 69008 France

Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA 98109 1024 USA; Division of Pediatric Hematology Oncology University of Washington School of Medicine Seattle Children's Hospital Seattle WA 98145 5005 USA

Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong Shatin New Territories Hong Kong China

Department of Computer Science University of Toronto Toronto ON M5S 2E4 Canada; Program in Genetics and Genome Biology The Hospital for Sick Children Toronto ON M5G 1X8 Canada

Department of Hematology and Medical Oncology School of Medicine and Winship Cancer Institute Emory University Atlanta GA 30322 USA

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN 55905 USA

Department of Neuro Oncology Istituto Neurologico Besta Milan 20133 Italy

Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh PA 15213 USA

Department of Neurological Surgery Vanderbilt Medical Center Nashville TN 37232 USA

Department of Neurology Erasmus University Medical Center Rotterdam 3015 CE the Netherlands

Department of Neurology Vanderbilt Medical Center Nashville TN 37232 USA

Department of Neurosurgery Chonnam National University Research Institute of Medical Sciences Chonnam National University Hwasun Hospital and Medical School Hwasun gun 519 763 Chonnam South Korea

Department of Neurosurgery David Geffen School of Medicine at UCLA Los Angeles CA 90095 USA

Department of Neurosurgery Division of Pediatric Neurosurgery Seoul National University Children's Hospital Seoul 30322 South Korea

Department of Neurosurgery Erasmus University Medical Center Rotterdam 3015 CE the Netherlands

Department of Neurosurgery Hospital Infantil de Mexico Federico Gomez Mexico City 06720 Mexico

Department of Neurosurgery Kitasato University School of Medicine Sagamihara Kanagawa 252 0374 Japan

Department of Neurosurgery Kumamoto University Graduate School of Medical Science Kumamoto 860 8555 Japan

Department of Neurosurgery University of Debrecen Medical and Health Science Centre Debrecen 4032 Hungary

Department of Neurosurgery University of Ulsan Asan Medical Center Seoul 05505 South Korea

Department of Oncology The Children's Memorial Health Institute University of Warsaw Warsaw 04 730 Poland

Department of Pathology and Laboratory Medicine University of Calgary Calgary AB T2N 2T9 Canada

Department of Pathology Erasmus University Medical Center Rotterdam 3015 CN the Netherlands

Department of Pathology Hospital Infantil de Mexico Federico Gomez Mexico City 06720 Mexico

Department of Pathology McGill University Montreal QC H4A 3J1 Canada; Department of Pathology Montreal Children's Hospital Montreal QC H4A 3J1 Canada

Department of Pathology The Children's Memorial Health Institute University of Warsaw Warsaw 04 730 Poland

Department of Pathology University of Arkansas for Medical Sciences Little Rock AR 72205 USA

Department of Pathology University of Pittsburgh School of Medicine Pittsburgh PA 15261 USA

Department of Pediatric Neurosurgery Catholic University Medical School Rome 00198 Italy

Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty University Hospital Düsseldorf Düsseldorf 40225 Germany; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON M5S 1A1 Canada; Department of Pediatric Neuro Oncogenomics German Cancer Consortium Düsseldorf 40225 Germany

Department of Pediatric Oncology School of Medicine Masaryk University Brno 625 00 Czech Republic

Department of Pediatrics University of Colorado Denver Aurora CO 80045 USA

Department of Pediatrics Virginia Commonwealth University School of Medicine Richmond VA 23298 0646 USA

Department of Surgery and Anatomy Faculty of Medicine of Ribeirão Preto University of São Paulo São Paulo 14049 900 Brazil

Department of Surgery Division of Neurosurgery University of Alabama at Birmingham Birmingham AL 35233 USA

Departments of Pathology Ophthalmology and Oncology John Hopkins University School of Medicine Baltimore MD 21287 USA

Departments of Pediatrics Anatomy and Neurobiology Washington University School of Medicine and St Louis Children's Hospital St Louis MO 63110 USA

Departments of Pediatrics Neurological Surgery and Neurology University of California San Francisco San Francisco CA 94143 0112 USA

Developmental Tumor Biology Laboratory Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona 08950 Spain

Dipartimento di Biochimica e Biotecnologie Mediche University of Naples Naples 80145 Italy

Division of Anatomical Pathology Department of Pathology and Molecular Medicine McMaster University Hamilton ON L8S 4K1 Canada; Department of Pathology and Laboratory Medicine Hamilton General Hospital Hamilton ON L8L 2X2 Canada

Division of Haematology Oncology The Hospital for Sick Children Toronto ON M5G 1X8 Canada

Division of Hematology Oncology Department of Pediatrics McGill University Montreal QC H4A 3J1 Canada

Division of Hematology Oncology University of Cincinnati Cincinnati Children's Hospital Medical Center Cincinnati OH 45229 USA

Division of Neurosurgery Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon 1649 035 Portugal

Division of Pediatric Hematology Oncology Hospital Pediatría Centro Médico Nacional Century XXI Mexico City 06720 Mexico

Division of Pediatric Hematology Oncology Mayo Clinic Rochester MN 55905 USA

Division of Pediatric Hematology Oncology University of Washington School of Medicine Seattle Children's Hospital Seattle WA 98145 5005 USA

Division of Pediatric Neurosurgery Department of Neurosurgery Saint Louis University School of Medicine St Louis MO USA

Division of Pediatric Neurosurgery Department of Neurosurgery Washington University School of Medicine and St Louis Children's Hospital St Louis MO 63110 USA

Division of Pediatric Neurosurgery Rainbow and Babies Children's Hospital Case Western Reserve Cleveland OH 44106 USA

Division of Stem Cell Research Institute for Clinical Research Osaka National Hospital Osaka 540 0006 Japan

Divison of Pathology Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon 1649 035 Portugal

Fondazione IRCCS Istituto Nazionale Tumori Milan 20133 Italy

Informatics Program Ontario Institute for Cancer Research Toronto ON M5G 0A3 Canada; Department of Medical Biophysics University of Toronto Toronto ON M5G 1L7 Canada

Institute of Pediatric Hematology and Oncology Lyon 69008 France

Kolling Institute of Medical Research The University of Sydney Sydney NSW 2065 Australia

Lady Cilento Children's Hospital The University of Queensland Brisbane QLD 4102 Australia; Oncology Service Children's Health Queensland Hospital and Health Service South Brisbane QLD 4029 Australia

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON M5S 1A1 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON M5S 1A1 Canada; Division of Neurosurgery The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON M5S 1A1 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON M5S 1A1 Canada; Division of Neurosurgery The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Division of Haematology Oncology The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Division of Haematology Oncology The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Program in Neuroscience and Mental Health and Division of Neurology The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Division of Neurosurgery The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 1X8 Canada; Division of Pathology The Hospital for Sick Children Toronto ON M5G 1X8 Canada

The Donnelly Centre University of Toronto Toronto ON M5S 3E1 Canada; Banting and Best Department of Medical Research University of Toronto Toronto ON M5G 1L6 Canada; McLaughlin Centre University of Toronto Toronto ON M5G 0A4 Canada; Department of Molecular Genetics University of Toronto Toronto ON M5S 1A8 Canada; Samuel Lunenfeld Research Institute at Mount Sinai Hospital University of Toronto Toronto ON M5G 1X5 Canada

UPCI Brain Tumor Program University of Pittsburgh Children's Hospital of Pittsburgh Pittsburgh PA 15224 USA

Komentář v

Cancer Cell. 2017 Jun 12;31(6):727-729. doi: 10.1016/j.ccell.2017.05.013. PubMed

Zobrazit více v PubMed

Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA Methylation microarrays. Bioinformatics. 2014;30:1363–1369. PubMed PMC

Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, Rheinbay E, Miller CR, Vitucci M, Morozova O, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481–2498. PubMed PMC

Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol. 2011;29:1424–1430. PubMed PMC

Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W, Chmielecki J, Beer DG, Cope L, Creighton CJ, Danilova L, et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–550. PubMed PMC

Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG, Bunney WE, Myers RM, Speed TP, Akil H, et al. Evolving gene/transcript definitions significantly alter the interpretation of genechip data. Nucleic Acids Res. 2005;33:e175. PubMed PMC

Gaujoux R, Seoighe C. A flexible R package for nonnegative matrix factorization. BMC Bioinformatics. 2010;11:367. PubMed PMC

Gautier L, Cope L, Bolstad BM, Irizarry RA. affy — analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–315. PubMed

Gevaert O. MethylMix: an R package for identifying DNA methylation-driven genes. Bioinformatics. 2015;31:1839–1841. PubMed PMC

Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G, et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 2013;125:913–916. PubMed PMC

Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MD, Niu B, McLellan MD, Uzunangelov V, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158:929–944. PubMed PMC

Kauffmann A, Gentleman R, Huber W. arrayQualityMetrics – a bioconductor package for quality assessment of microarray data. Bioinformatics. 2009;25:415–416. PubMed PMC

Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393–405. PubMed PMC

Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, Ramaswamy V, Finlay J, Taylor MD, Dhall G, et al. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy. Pediatr Blood Cancer. 2016;63:1527–1534. PubMed PMC

Lex A, Streit M, Schulz HJ, Partl C, Schmalstieg D, Park PJ, Gehlenborg N. StratomeX: visual analysis of large-scale heterogeneous genomics data for cancer subtype characterization. Computer Graphics Forum. 2012;31:1175–1184. PubMed PMC

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–820. PubMed

Maksimovic J, Gordon L, Oshlack A. SWAN: subset-quantile within array normalization for Illumina Infinium HumanMethylation450 BeadChips. Genome Biol. 2012;13:R44. PubMed PMC

Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS One. 2010;5:e13984. PubMed PMC

Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12:R41. PubMed PMC

Mo Q, Wang S, Seshan VE, Olshen AB, Schultz N, Sander C, Powers RS, Ladanyi M, Shen R. Pattern discovery and cancer gene identification in integrated cancer genomic data. Proc Natl Acad Sci USA. 2013;110:4245–4250. PubMed PMC

Morrissy AS, Garzia L, Shih DJ, Zuyderduyn S, Huang X, Skowron P, Remke M, Cavalli FM, Ramaswamy V, Lindsay PE, et al. Divergent clonal selection dominates medulloblastoma at recurrence. Nature. 2016;529:351–357. PubMed PMC

Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, Al-Halabi H, Albrecht S, Jabado N, Eberhart CG, et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol. 2011;122:231–240. PubMed PMC

Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012a;12:818–834. PubMed PMC

Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, Korshunov A, Reimand J, Schumacher SE, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012b;488:49–56. PubMed PMC

Northcott PA, Lee C, Zichner T, Stutz AM, Erkek S, Kawauchi D, Shih DJ, Hovestadt V, Zapatka M, Sturm D, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. 2014;511:428–434. PubMed PMC

Pei Y, Liu KW, Wang J, Garancher A, Tao R, Esparza LA, Maier DL, Udaka YT, Murad N, Morrissy S, et al. HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell. 2016;29:311–323. PubMed PMC

Ramaswamy V, Northcott PA, Taylor MD. FISH and chips: the recipe for improved prognostication and outcomes for children with medulloblastoma. Cancer Genet. 2011;204:577–588. PubMed

Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho YJ, Shih DJ, Luu B, Dubuc AM, Northcott PA, et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol. 2013;14:1200–1207. PubMed PMC

Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, Kool M, Dufour C, Vassal G, Milde T, et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol. 2016a;131:821–831. PubMed PMC

Ramaswamy V, Remke M, Adamski J, Bartels U, Tabori U, Wang X, Huang A, Hawkins C, Mabbott D, Laperriere N, et al. Medulloblastoma subgroup-specific outcomes in irradiated children: who are the true high-risk patients? Neuro Oncol. 2016b;18:291–297. PubMed PMC

Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, Vilo J. g:Profiler – a web server for functional interpretation of gene lists (2016 update) Nucleic Acids Res. 2016;44:W83–W89. PubMed PMC

Remke M, Hielscher T, Northcott PA, Witt H, Ryzhova M, Wittmann A, Benner A, von Deimling A, Scheurlen W, Perry A, et al. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol. 2011;29:2717–2723. PubMed

Remke M, Ramaswamy V, Peacock J, Shih DJ, Koelsche C, Northcott PA, Hill N, Cavalli FM, Kool M, Wang X, et al. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathol. 2013;126:917–929. PubMed PMC

Rutkowski S, Cohen B, Finlay J, Luksch R, Ridola V, Valteau-Couanet D, Hara J, Garre ML, Grill J. Medulloblastoma in young children. Pediatr Blood Cancer. 2010;54:635–637. PubMed

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–2504. PubMed PMC

Shen R, Olshen AB, Ladanyi M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics. 2009;25:2906–2912. PubMed PMC

Streit M, Lex A, Gratzl S, Partl C, Schmalstieg D, Pfister H, Park PJ, Gehlenborg N. Guided visual exploration of genomic stratifications in cancer. Nat Methods. 2014;11:884–885. PubMed PMC

Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22:425–437. PubMed

Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–472. PubMed PMC

Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, McLendon RE, Bigner DD, Lipp ES, Perreault S, et al. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol. 2016;17:484–495. PubMed PMC

Wang B, Mezlini AM, Demir F, Fiume M, Tu Z, Brudno M, Haibe-Kains B, Goldenberg A. Similarity network fusion for aggregating data types on a genomic scale. Nat Methods. 2014;11:333–337. PubMed

Wilkerson DM, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010;26:1572–1573. PubMed PMC

Zhao F, Ohgaki H, Xu L, Giangaspero F, Li C, Li P, Yang Z, Wang B, Wang X, Wang Z, et al. Molecular subgroups of adult medulloblastoma: a long-term single-institution study. Neuro Oncol. 2016;18:982–990. PubMed PMC

Zhou W, Laird PW, Shen H. Comprehensive characterization, annotation and innovative use of Infinium DNA Methylation BeadChip probes. Nucleic Acids Res. 2016;45:e22. PubMed PMC

Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, Castelo-Branco P, Baskin B, Ray PN, Bouffet E, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol. 2013;31:2927–2935. PubMed PMC

Zou H, Hastie T. Regularization and variable selection via the elastic net. J R Stat Soc Ser B. 2005;67:301–320.

Comparative analysis of pediatric SHH medulloblastoma DAOY spheres and adherent monolayers: implications for medulloblastoma research

Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma

Failure of human rhombic lip differentiation underlies medulloblastoma formation

The transcriptional landscape of Shh medulloblastoma

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma