title: Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas.
abstract: The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development.
  
  
  
  We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing.
  
  
  
  Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations.
  
  
  
  Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy.
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors.forename: Khalil
authors.initials: K
authors.lastname: Abou-El-Ardat
authors.affiliation: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.|Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Becker
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Eisenreich
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Meijer
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.affiliation: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.|Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
authors.affiliation: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.|Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.affiliation: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.|Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D060965:Clonal Evolution; D019143:Evolution, Molecular; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D009154:Mutation; D015398:Signal Transduction
keywords: monoclonal origin; multifocal glioblastoma; tumor evolution; tumor genetics; tumor heterogeneity