Gene amplification mechanisms
Gene amplification mechanisms
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DOI：
10.1007/1-4020-3764-3_12
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Malfoy, B
中科院分区：
文献类型：
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作者：
Debatisse, M;Malfoy, B
基因扩增是癌症中发现的最常见的基因组改变之一。这种现象首先由Alt等人在哺乳动物细胞中表征，他研究了在体外选择的抵抗甲氨蝶呤（MTX）的突变体，甲氨蝶呤是二氢叶酸还原酶（DHFR）的抑制剂（Alt等，1978年）。抗性通常是由于DHFR基因拷贝数的增加，这导致了蛋白质的过量产生。突变体的细胞遗传学分析表明，扩增的拷贝位于异常的染色体结构上。Biedler和Spengler首先报道了在扩增DHFR基因的中国仓鼠细胞中存在染色体扩增，称为HSR（均匀染色区域）（Biedler和Spengler，1976）。扩增的拷贝可替代地积累为着丝粒缺陷的染色体外环状元件，称为双微体（DM）（考夫曼等人，1979年）。在通过各种细胞毒性药物选择后针对不同基因座扩增的突变细胞中也发现了HSR和DM（Stark和Wahl，1984）。大量的报告强调在肿瘤细胞和已建立的肿瘤细胞系中存在相同类型的异常结构。对肿瘤集合进行候选癌基因的分子筛选，确定属于MYC、ERBB、FGFR和RAS家族的基因在这些细胞中反复扩增（Brison，1993; Schwab和Amler，1990）。通过基因组方法对肿瘤中扩增的基因的全球搜索现在表明，编码有利于细胞增殖的蛋白质的大多数基因，包括参与细胞周期进程的那些基因和一些管家基因，可以在生长的肿瘤中被选择（Knuutila等人，1998; Schwab，1999）。基因扩增通常在肿瘤中发现，但在正常细胞中不存在。事实上，当研究同一患者的肿瘤细胞和正常细胞时，
Gene amplification is one of the most frequent genomic alterations found in cancer. This phenomenon has been first characterised in mammalian cells by Alt et al., who studied mutants selected in vitro to resist metothrexate (MTX), an inhibitor of the dihydrofolate reductase (DHFR)(Alt et al., 1978). Resistance was often due to an increase in the copy number of the DHFR gene, which leads to overproduce the protein. Cytogenetic analysis of mutants showed that amplified copies lie on abnormal chromosomal structures. Biedler and Spengler first reported on the presence of chromosome expansions, called HSRs (homogeneously staining regions), in Chinese hamster cells amplified for the DHFR gene (Biedler and Spengler, 1976). The amplified copies may alternatively accumulate as centromeredeficient extra-chromosomal circular elements, called double-minutes (DMs)(Kaufman et al., 1979). HSRs and DMs were also found in mutant cells amplified for different loci following selection by various cytotoxic drugs (Stark and Wahl, 1984). A large number of reports stressed the presence of the same types of abnormal structures in cells of tumours and established tumour cell lines. Molecular screening of collections of tumours for candidate oncogenes established that genes belonging to the MYC, ERBB, FGFR and RAS families are recurrently amplified in these cells (Brison, 1993; Schwab and Amler, 1990). Global searches for genes amplified in tumours by genomic approaches now suggest that most genes coding for proteins that favour cell proliferation, including those involved in cell cycle progression and some house keeping genes, may be selected for in growing tumours (Knuutila et al., 1998; Schwab, 1999). Gene amplification is commonly found in tumour but not in normal cells. Indeed, when both tumour and normal cells of the same patient were studied,