51. Extrachromosomal driver mutations in glioblastoma and low-grade glioma
- Author
-
Ivan Radovanovic, Françoise Forestier, Karl Lothard Schaller, Emilie Falconnet, Anne Vannier, Marco Garieri, Michel Guipponi, Virginie Clément-Schatlo, Pierre-Yves Dietrich, Stylianos E. Antonarakis, Valérie Dutoit, Periklis Makrythanasis, Sergey Nikolaev, Federico Santoni, and Frédérique Béna
- Subjects
Genome instability ,General Physics and Astronomy ,PDGFRA ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Genomic Instability ,Article ,Glioma ,Extrachromosomal DNA ,Gene duplication ,medicine ,Humans ,ddc:576.5 ,Exome sequencing ,Genetics ,Mutation ,Multidisciplinary ,Brain Neoplasms ,fungi ,Gene Amplification ,General Chemistry ,medicine.disease ,3. Good health ,Cancer cell ,Cancer research ,DNA, Circular ,Neoplasm Grading ,Glioblastoma - 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.
- Published
- 2014