title: Extrachromosomal driver mutations in glioblastoma and low-grade glioma.
abstract: Alteration of the number of copies of double minutes (DMs) with oncogenic EGFR mutations in response to tyrosine kinase inhibitors is a novel adaptive mechanism of glioblastoma. Here 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 seven glioblastoma patients we reveal ALEMs in EGFR, PDGFRA and other genes. These mutations together with DMs are lost by cancer cells in culture. We confirm the extrachromosomal origin of such mutations by showing that wild-type and mutated DMs may coexist in the same tumour. Analysis of 4,198 tumours suggests the presence of ALEMs across different tumour 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.
authors.affiliation: Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nikolaev
authors.affiliation: Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.|Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.affiliation: Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garieri
authors.affiliation: Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.|Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.affiliation: Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.affiliation: Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Vannier
authors.affiliation: Department of Clinical Neuroscience. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.|Department of Neurosurgery, Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Radovanovic
authors.affiliation: Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.
authors.forename: Frederique
authors.initials: F
authors.lastname: Bena
authors.affiliation: Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.
authors.forename: Françoise
authors.initials: F
authors.lastname: Forestier
authors.affiliation: Department of Clinical Neuroscience. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.|Department of Neurosurgery, Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Schaller
authors.affiliation: Center of Oncology. Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Dutoit
authors.affiliation: Department of Clinical Neuroscience. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.|Department of Neurosurgery, Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland.
authors.forename: Virginie
authors.initials: V
authors.lastname: Clement-Schatlo
authors.affiliation: Center of Oncology. Geneva University Hospitals - HUG. 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 4, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
authors.affiliation: Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.|Geneva University Hospitals - HUG. Service of Genetic Medicine. 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland.|IGE3 institute of Genetics and Genomics of Geneva. 1 rue Michel Servet, 1211.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D004270:DNA, Circular / Q000235:genetics*; D005784:Gene Amplification; D042822:Genomic Instability; D005909:Glioblastoma / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading
chemical_list: D004270:DNA, Circular