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Nat Commun. 2014 Dec 4;5:5690. doi: 10.1038/ncomms6690.

Extrachromosomal driver mutations in glioblastoma and low-grade glioma.

Author information

1
Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, 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.
#
Contributed equally

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.

PMID:
25471132
PMCID:
PMC4338529
DOI:
10.1038/ncomms6690
[Indexed for MEDLINE]
Free PMC Article

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