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Extrachromosomal driver mutations in glioblastoma and low-grade glioma
Sergey Nikolaev1, Federico Santoni1,2, Marco Garieri1
1Department of Genetic Medicine and Development. University of Geneva Medical School. 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
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.
Insights
Glioblastoma cancer cells adapt by altering double minutes (DMs) carrying EGFR mutations. These amplification-linked extrachromosomal mutations (ALEMs) can be eliminated, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Cancer Genetics
- Molecular Biology
Background:
- Glioblastoma exhibits adaptive mechanisms involving oncogenic mutations.
- Double minutes (DMs) are extrachromosomal elements associated with gene amplification in cancer.
- Tyrosine kinase inhibitors (TKIs) can induce alterations in DM copy number.
Purpose of the Study:
- To investigate the origin and behavior of mutations within DMs in glioblastoma.
- To characterize amplification-linked extrachromosomal mutations (ALEMs).
- To determine the prevalence and implications of ALEMs in various tumor types.
Main Methods:
- Exome sequencing of glioblastoma patient samples.
- In vitro culture of cancer cells to observe DM and mutation dynamics.
- Analysis of a large tumor dataset (4,198 samples).
Main Results:
- Identified ALEMs in EGFR, PDGFRA, and other genes in glioblastoma.
- Demonstrated that ALEMs and DMs can be lost from cancer cells.
- Confirmed extrachromosomal origin of ALEMs, with coexistence of wild-type and mutated DMs.
- Found ALEMs in various tumor types, notably glioblastomas and low-grade gliomas.
Conclusions:
- ALEMs originate extrachromosomally and can be eliminated from cancer cells.
- The extrachromosomal nature of ALEMs explains dynamic changes in oncogene mutation levels.
- ALEMs represent a significant factor in glioblastoma adaptation and therapeutic response.
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