Extrachromosomal amplification mechanisms in a glioma with amplified sequences from multiple chromosome loci
Extrachromosomal amplification mechanisms in a glioma with amplified sequences from multiple chromosome loci
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DOI：
10.1093/hmg/ddq004
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发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Malfoy, Bernard
中科院分区：
文献类型：
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作者：
Gibaud, Anne;Vogt, Nicolas;Malfoy, Bernard
染色体外DNA分子的积累(双分钟)通常是癌症中基因放大的原因，但导致它们形成的机制在很大程度上仍不清楚。采用定量聚合酶链式反应、染色体走行、中期染色体原位杂交和全基因组分析等方法，对一例含有7p11、1q32.1、5p15和9p2四个染色体外扩增位点的胶质瘤进行了研究。从7p11、5p15到9p2的多个共线或非共线DNA片段融合形成复杂的染色体外DNA分子。片段的范围从几个碱基对到百万碱基对。扩增过程中留下的疤痕以缺失或染色体重排的形式保留在原始基因座上。复制压力引起的染色体碎裂可以解释这种复杂的情况。相反，在1q32.1，最初的染色体外DNA分子是由与染色体内缺失相关的单个片段的环化导致的，包括但大于扩增的序列。这些重排所涉及的序列的性质表明，V(D)J类非法重组有助于其形成。
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.