title: Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.
abstract: Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
authors.affiliation: Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha P.O. box 5825, Qatar; Department of Science and Technology, University of Sannio, Benevento 82100, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Oncology Graduate School Amsterdam, Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.
authors.forename: Floris P
authors.initials: FP
authors.lastname: Barthel
authors.affiliation: Department of Genetics (CISBi/NAP), Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil; Center for Integrative Systems Biology (CISBi, NAP/USP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Tathiane M
authors.initials: TM
authors.lastname: Malta
authors.affiliation: Department of Genetics (CISBi/NAP), Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil; Center for Integrative Systems Biology (CISBi, NAP/USP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Thais S
authors.initials: TS
authors.lastname: Sabedot
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Sofie R
authors.initials: SR
authors.lastname: Salama
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Murray
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Olena
authors.initials: O
authors.lastname: Morozova
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Newton
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Amie
authors.initials: A
authors.lastname: Radenbaugh
authors.affiliation: Department of Science and Technology, University of Sannio, Benevento 82100, Italy; BIOGEM Istituto di Ricerche Genetiche "G. Salvatore," Campo Reale, 83031 Ariano Irpino, Italy.
authors.forename: Stefano M
authors.initials: SM
authors.lastname: Pagnotta
authors.affiliation: Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha P.O. box 5825, Qatar.
authors.forename: Samreen
authors.initials: S
authors.lastname: Anjum
authors.affiliation: Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Department of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ganiraju
authors.initials: G
authors.lastname: Manyam
authors.affiliation: Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Department of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
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authors.initials: P
authors.lastname: Zoppoli
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shiyun
authors.initials: S
authors.lastname: Ling
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Arjun A
authors.initials: AA
authors.lastname: Rao
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Mia
authors.initials: M
authors.lastname: Grifford
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Laila
authors.initials: L
authors.lastname: Poisson
authors.affiliation: Department of Genetics (CISBi/NAP), Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil; Center for Integrative Systems Biology (CISBi, NAP/USP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Carlos Gilberto
authors.initials: CG
authors.lastname: Carlotti
authors.affiliation: Department of Genetics (CISBi/NAP), Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil; Center for Integrative Systems Biology (CISBi, NAP/USP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Daniela Pretti da Cunha
authors.initials: DP
authors.lastname: Tirapelli
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Rao
authors.affiliation: Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Texas Children's Hospital, Houston, TX 77030, USA; Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.affiliation: Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Department of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Huse
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
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authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Lehman
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
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authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Cooper
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Akbani
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Wrensch
authors.affiliation: UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: David
authors.initials: D
authors.lastname: Haussler
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: School of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.affiliation: Department of Genetics (CISBi/NAP), Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Monte Alegre, Ribeirão Preto-SP CEP: 14049-900, Brazil; Center for Integrative Systems Biology (CISBi, NAP/USP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil. Electronic address: houtan@usp.br.
authors.forename: Houtan
authors.initials: H
authors.lastname: Noushmehr
authors.affiliation: Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Department of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: ai2102@columbia.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, Department of Biostatistics, Department of Neuro-Oncology, Department of Neurosurgery, Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rverhaak@mdanderson.org.
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D016000:Cluster Analysis; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics; D016615:Telomere; D059467:Transcriptome; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D007521:Isocitrate Dehydrogenase; C509186:TERT protein, human; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
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