Extrachromosomal amplification mechanisms in a glioma with amplified sequences from multiple chromosome loci.
Accumulation of extrachromosomal DNA molecules (double minute) is often responsible for gene amplification in cancers, but the mechanisms leading to their formation are still largely unknown. By using quantitative PCR, chromosome walking, in situ hybridization on metaphase chromosomes and whole genome analysis, we studied a glioma containing four extrachromosomally amplified loci (7p11, 1q32.1, 5p15 and 9p2). Complex extrachromosomal DNA molecules were formed by the fusion of several syntenic or non-syntenic DNA fragments from 7p11, 5p15 to 9p2. Fragments ranged from a few base pairs to megabase pairs. Scars of the amplification process remained at the original locus in the form of deletions or chromosome rearrangements. Chromosome fragmentation, due to replication stress, could explain this complex situation. In contrast, at 1q32.1, the initial extrachromosomal DNA molecule resulted from the circularization of a single fragment associated with an intrachromosomal deletion including, but larger than, the amplified sequence. The nature of the sequences involved in these rearrangements suggests that a V(D)J-like illegitimate recombination contributes to its formation.
Gibaud
Anne
A
Centre de Recherche, Institut Curie, Paris, France.
Vogt
Nicolas
N
Hadj-Hamou
Nabila-Sandra
NS
Meyniel
Jean-Philippe
JP
Hupé
Philippe
P
Debatisse
Michelle
M
Malfoy
Bernard
B
D001932:Brain Neoplasms / Q000235:genetics; D002872:Chromosome Deletion; D022004:Chromosome Structures; D002878:Chromosomes, Human, Pair 1; D005111:Extrachromosomal Inheritance; D005784:Gene Amplification; D005910:Glioma / Q000235:genetics*; D006801:Humans; D009693:Nucleic Acid Hybridization