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Cancer Cell. 2019 Apr 15;35(4):692-704.e12. doi: 10.1016/j.ccell.2019.02.007. Epub 2019 Mar 21.

Evolutionary Trajectories of IDHWT Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis.

Author information

1
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Bioquant Center, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
2
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
3
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
4
Division of Molecular Genetics, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
5
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
6
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
7
Division of Molecular Genetics, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
8
Pediatric Glioma Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
9
Institut für Medizinische Informatik, Statistik und Epidemiologie, Universität Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany.
10
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Neues Klinikum O10, Martinistr. 52, 20246 Hamburg, Germany.
11
Department of Neurosurgery, Ludwig Maximilians University Munich and German Cancer Consortium (DKTK), partner site Munich, Marchioninistraße 15, 81377 Munich, Germany.
12
Department of Neurosurgery, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
13
Department of Neurosurgery, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40255 Düsseldorf, Germany.
14
Institute of Neuropathology, Heinrich Heine University Düsseldorf, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Moorenstr. 5, 40255 Düsseldorf, Germany.
15
Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
16
Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, 8091 Zurich, Switzerland.
17
Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
18
Institute of Neuropathology, Heinrich Heine University Düsseldorf, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Moorenstr. 5, 40255 Düsseldorf, Germany. Electronic address: guido.reifenberger@med.uni-duesseldorf.de.
19
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Bioquant Center, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany. Electronic address: t.hoefer@dkfz.de.
20
Division of Molecular Genetics, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: peter.lichter@dkfz.de.

Abstract

We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. TERT promoter mutations often occurred later as a prerequisite for rapid growth. In contrast to this common early path, relapsed tumors acquired no stereotypical pattern of mutations and typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures.

KEYWORDS:

cancer evolution; clonal dynamics; glioblastoma; selective advantage; tumor growth; tumor phylogenetics; tumor recurrence

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