[en] A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.
Disciplines :
Genetics & genetic processes
Author, co-author :
Hoogstrate, Youri ; Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands. Electronic address: y.hoogstrate@erasmusmc.nl
Draaisma, Kaspar; Department of Neurosurgery, UMC Utrecht, 3584CX Utrecht, the Netherlands
Ghisai, Santoesha A; Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
van Hijfte, Levi; Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands, Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Barin, Nastaran; Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands, Department of Precision and Microsystems Engineering, Delft University of Technology, 2628CD Delft, the Netherlands
de Heer, Iris; Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
van den Bosch, Thierry P P; Department of Pathology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Bolleboom, Anne; Deparment of Neuroscience, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands, Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Gao, Zhenyu; Deparment of Neuroscience, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Vincent, Arnaud J P E; Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Deckers, Manon ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale
Taphoorn, Martin J B; Department of Neurology, Haaglanden Medical Center, 2512VA The Hague, the Netherlands, Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
Kerkhof, Melissa; Department of Neurology, Haaglanden Medical Center, 2512VA The Hague, the Netherlands
Weyerbrock, Astrid; Department of Neurosurgery, Medical Center - University of Freiburg, 79106 Freiburg, Germany, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
Sanson, Marc; Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France
Hoeben, Ann; Department of Internal Medicine, Division of Medical Oncology, GROW, Maastricht University Medical Center, 6229ER Maastricht, the Netherlands
Lukacova, Slávka; Department of Oncology, Aarhus University Hospital, 8200 Aarhus, Denmark
Lombardi, Giuseppe; Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
Leenstra, Sieger; Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Hanse, Monique; Department of Neurology, Catharina Hospital, 5623EJ Eindhoven, the Netherlands
Fleischeuer, Ruth E M; Department of Pathology, Elisabeth-TweeSteden Hospital, 5042AD Tilburg, the Netherlands
Watts, Colin; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, B15 2SY Birmingham, UK
Angelopoulos, Nicos; Systems Immunity Research Institute, Medical School, Cardiff University, CF14 4XN Cardiff, UK
This project has been funded by De Westlandse Ride and The Brain Tumour Charity grant number ET_2019/2_10470 and Télévie grant number 7.6514.17 from Belgium. N.A. is supported by the Ser Cymru II program, which is partly funded by Cardiff University and the European Regional Development Fund through the Welsh Government . The graphical abstract was made using BioRender.com .
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