Extrachromosomal driver mutations in glioblastoma and low-grade glioma

Article Article scientifique Article Extrachromosomal driver mutations in glioblastoma and low-grade glioma eng 2014 author Nikolaev Sergey Igorievich 593779 author Santoni Federico 681638 author Garieri Marco 794768 author Makrythanasis Periklis 638085 author Falconnet Emilie 656349 author Guipponi Michel 118157 author Vannier Anne 751929 author Radovanovic Ivan 58555 author Sloan Bena Frédérique 629243 author Forestier Felix Françoise 513697 author Schaller Karl Lothard 658606 author Dutoit Vallotton Valérie 0000-0002-3469-4237 668630 author Clement-Schatlo Virginie author Dietrich Pierre-Yves 96532 author Antonarakis Stylianos 22813 5690 10.1038/ncomms6690 25471132 2041-1723 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. Dewey 576.5 135 Département de médecine génétique et développement 21D false 513 Groupe Schaller Karl Lothard (neurochirurgie) 851 27 Immunothérapie des cancers 42 196 Pathologie Moléculaire de la Trisomie 21 et le Génome Humain 248 Nature communications 5 02333ad1-ab4a-4385-a17d-2efa617c207e Article (Published version) Public ncomms6690.pdf 751167 application/pdf openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Extrachromosomal driver mutations in glioblastoma and low-grade glioma	Nature communications			2014	775	274

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