Significance of multiple mutations in cancer
Significance of multiple mutations in cancer
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DOI：
10.1093/carcin/21.3.379
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发表时间：
2000-03-01
期刊：
影响因子：
4.7
通讯作者：
Loeb, LA
中科院分区：
文献类型：
--
作者：
Loeb, KR;Loeb, LA
越来越多的证据表明，在真核细胞中，DNA经历连续的损伤、修复和再合成，存在一种稳态平衡，其中广泛的DNA损伤被多种DNA修复途径抵消。在正常细胞中，大多数DNA损伤都能被修复而不会出错。然而，在肿瘤细胞中，这种平衡可能会被扭曲，导致多个突变的积累。突变的基因是那些在保证基因组稳定性方面发挥作用的基因。这种稳定性的丧失导致突变子表型。人类癌症中突变子表型的证据包括基因扩增、微卫星不稳定性、染色体畸变和非整倍性的频繁发生。目前的实验集中在两个机制的产生基因组不稳定性，一个集中在错配修复基因的突变导致微卫星不稳定性，和一个集中在基因突变所需的染色体分离导致染色体畸变。这种二分法可能只反映了这些表现可以被识别的容易性。这两种途径的基础可能是一个更普遍的现象，涉及在肿瘤进展过程中对增变基因的选择。在癌发生过程中，存在对携带突变的细胞的选择，这些突变可以克服限制肿瘤生长的不利条件。这些突变由直接DNA损伤产生，以及其次作为导致增变子表型的基因突变的结果。因此，当肿瘤进展选择具有特定突变的细胞时，它也选择在正常情况下维持遗传不稳定性的基因中携带突变的癌细胞。
There is increasing evidence that in eukaryotic cells, DNA undergoes continuous damage, repair and resynthesis, A homeostatic equilibrium exists in which extensive DNA damage is counterbalanced by multiple pathways for DNA repair. In normal cells, most DNA damage is repaired without error. However, in tumor cells this equilibrium may be skewed, resulting in the accumulation of multiple mutations. Among genes mutated are those that function in guaranteeing the stability of the genome. Loss of this stability results in a mutator phenotype. Evidence for a mutator phenotype in human cancers includes the frequent occurrence of gene amplification, microsatellite instability, chromosomal aberrations and aneuploidy. Current experiments have centered on two mechanisms for the generation of genomic instability, one focused on mutations in mismatch repair genes resulting in microsatellite instability, and one focused on mutations in genes that are required for chromosomal segregation resulting in chromosomal aberrations. This dichotomy may reflect only the ease by which these manifestations can be identified. Underlying both pathways may be a more general phenomenon involving the selection for mutator genes during tumor progression. During carcinogenesis there is selection for cells harboring mutations that can overcome adverse conditions that limit tumor growth. These mutations are produced by direct DNA damage as well as secondarily as a result of mutations in genes that cause a mutator phenotype. Thus, as tumor progression selects for cells with specific mutations, it also selects for cancer cells harboring mutations in genes that normally function in maintaining genetic instability.