Extrachromosomal driver mutations in glioblastoma and low grade glioma. S. I. Nikolaev1, F. Santoni1,2, M. Garieri1, P. Makrythanasis1, E. Falconnet1, M. Guipponi2, A. Vannier2, I. Radovanovic3,4, F. Bena2, K. Schaller3,4, V. Dutoit5, V. Clement-Schatlo3,4, P.-Y. Dietrich5, S. E. Antonarakis1,6 1) GeDev, University of Geneva, Geneva, Switzerland; 2) Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland; 3) Department of Clinical Neuroscience. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland; 4) Department of Neurosurgery, Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland; 5) Center of Oncology. Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland; 6) IGE3 institute of Genetics and Genomics of Geneva. 1 rue Michel Servet, 1211.

   Alteration of the number of copies of Double Minutes (DMs) with oncogenic EGFR mutations in response to tyrosine kinase inhibitors (TKIs) is a novel adaptive mechanism of glioblastoma. In this study we provide evidence that such mutations in DMs, called here Amplification Linked Extrachromosomal Mutations (ALEMs), originate extrachromosomally and could therefore be completely eliminated from the cancer cells. By exome sequencing of 7 glioblastoma patients we revealed ALEMs in EGFR, PDGFRA and other genes. These mutations together with DMs were lost by cancer cells in culture. We confirmed the extrachromosomal origin of such mutations by showing that wild type and mutated DMs may coexist in the same tumor. Analysis of 4198 tumors suggested the presence of ALEMs across different tumor types with the highest prevalence in glioblastomas and low grade gliomas. The extrachromosomal nature of ALEMs explains the observed drastic changes in the amounts of mutated oncogenes (like EGFR or PDGFRA) in glioblastoma in response to environmental changes.

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