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Extrachromosomal driver mutations in glioblastoma and low-grade glioma

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Published in Nature Communications. 2014, vol. 5, p. 5690
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.
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PMID: 25471132
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Article (Published version) (734 Kb) - public document Free access
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Research groups Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
Immunothérapie des cancers (42)
Groupe Schaller Karl Lothard (neurochirurgie) (851)
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NIKOLAEV, Sergey Igorievich et al. Extrachromosomal driver mutations in glioblastoma and low-grade glioma. In: Nature Communications, 2014, vol. 5, p. 5690. https://archive-ouverte.unige.ch/unige:44227

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Deposited on : 2014-12-23

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