Molecular Structure of Double-Minute Chromosomes Bearing Amplified Copies of the Epidermal Growth Factor Receptor Gene in Gliomas

Amplification of the epidermal growth factor receptor gene on double minutes is recurrently observed in cells of advanced gliomas, but the structure of these extrachromosomal circular DNA molecules and the mechanisms responsible for their formation are still poorly understood. By using quantitative...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (31), p.11368-11373
Main Authors: Vogt, Nicolas, Lefèvre, Sandrine-Hélène, Apiou, Françoise, Dutrillaux, Anne-Marie, Cör, Andrej, Leuraud, Pascal, Poupon, Marie-France, Dutrillaux, Bernard, Debatisse, Michelle, Malfoy, Bernard, Alt, Frederick W.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological Sciences
Brain Neoplasms - genetics
Brain Neoplasms - physiopathology
Cells
Chromosomes
Daughter cells
DNA
DNA, Circular
Gene Duplication
Genes
Genetic loci
Genetics
Genomes
Glioma
Glioma - genetics
Glioma - physiopathology
Humans
Mice
Mice, Nude
Molecular Sequence Data
Molecular structure
Molecules
Polymerase Chain Reaction
Receptor, Epidermal Growth Factor - genetics
Transplantation, Heterologous
Tumors
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Summary:Amplification of the epidermal growth factor receptor gene on double minutes is recurrently observed in cells of advanced gliomas, but the structure of these extrachromosomal circular DNA molecules and the mechanisms responsible for their formation are still poorly understood. By using quantitative PCR and chromosome walking, we investigated the genetic content and the organization of the repeats in the double minutes of seven gliomas. It was established that all of the amplicons of a given tumor derive from a single founding extrachromosomal DNA molecule. In each of these gliomas, the founding molecule was generated by a simple event that circularizes a chromosome fragment overlapping the epidermal growth factor receptor gene. In all cases, the fusion of the two ends of this initial amplicon resulted from microhomologybased nonhomologous end-joining. Furthermore, the corresponding chromosomal loci were not rearranged, which strongly suggests that a postreplicative event was responsible for the formation of each of these initial amplicons.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0402979101