Defects in replication fidelity of simple repeated sequences reveal a new mutator mechanism for oncogenesis.
Defects in replication fidelity of simple repeated sequences reveal a new mutator mechanism for oncogenesis.
复制标题
简单重复序列的复制保真度缺陷揭示了肿瘤发生的新突变机制。
DOI：
10.1101/sqb.1994.059.01.038
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Stanbridge,E
中科院分区：
文献类型：
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作者：
Perucho,M;Peinado,MA;Ionov,Y;Casares,S;Malkhosyan,S;Stanbridge,E
癌症的突变理论（Knudson 1971，1985）获得了压倒性的支持，因为种系和体细胞突变已被证明可以激活癌基因的恶性潜力，并使抑癌基因的抑制功能失活（Bishop 1991）。对这些肿瘤特异性突变的分析提供了有关致癌机制的基本信息，但对其病因学仍知之甚少。对于基因毒性物质的损伤和内源性 DNA 复制错误对癌症中这些突变的发生的相对贡献的估计，尚未达成一致（Ames 和 Gold 1990；Weinstein 1991）。 DNA复制中的自发错误可能是转化的基础这一概念被提出（Loeb et al. 1974；Cairns 1975），试图解释癌细胞的基因组不稳定性（Schimke et al. 1986；Cheng and Loeb 1993）。有缺陷的DNA复制因子可能会增加肿瘤进展过程中不断选择的肿瘤细胞变异的错误率（Foulds 1954；Nowell 1976）。然而，尽管付出了巨大的努力，这一假设的一个关键预测——肿瘤细胞突变频率的增加——仍然难以捉摸（Harris 1991；Loeb 1991）。 DNA复制和修复在转化中的重要性通过这些过程中的各种生化缺陷与易患癌症的遗传性疾病的关联得到了证明（Cleaver 1967；Lindahl et al. 1991）。涉及 DNA 合成和错误修复途径的编码因子的基因开始被分离和表征（Palombo 等人，1994 年；Tanaka 和 Wood 1994 年）。首次发现这些因素的突变与癌基因和抑癌基因突变的起源之间存在因果关系。结直肠癌是致癌过程多阶段性的最典型的例子之一。显性癌基因 c-Ki-ras 和至少三个不同的肿瘤抑制基因 p53、DCC 和 APC 始终参与结直肠肿瘤发生（Fearon 和 Vogelstein 1990；Fearon 和 Jones 1992）。除了这些关键基因的突变之外，结肠和直肠肿瘤还包含其他明显随机的遗传改变，这些改变在其范围内表现出显着的异质分布（Vogelstein 等人，1989）。高变人类小卫星序列的 DNA 指纹可用于不同个体之间多个基因座的比较分析（Jeffreys 等人，1985，1990）。小卫星位点的 DNA 指纹图谱检测到胃肠道肿瘤中偶尔发生的体细胞遗传改变（Thein 等人，1987 年；Armor 等人，1989 年；Vogelstein 等人，1989 年）。任意引物聚合酶链式反应 (AP-PCR) 是一种 DNA 指纹技术，其基础是使用单个任意引物 (Welsh 和 McClelland 1990) 通过 PCR 扩增多个 DNA 片段 (Welsh 和 McClelland 1990)。在一个简单的实验中可重复且定量地扩增许多匿名基因组序列，从而可以对细胞基因组进行公正的检查，并为分析伴随恶性肿瘤的遗传改变提供强大的工具。 AP-PCR 的 DNA 指纹分析揭示了一些结直肠肿瘤基因组中简单重复序列 (SRS) 处普遍存在的体细胞突变 (USM)（Peinado 等人，1992）。 SRS 的这些 USM 揭示了一种新的肿瘤发生突变机制，因为它们在 DNA 复制保真度的获得性或遗传性缺陷突变展开后积累，最终导致肿瘤形成（Ionov 等，1993）。在这里我们描述...
The mutational theory of cancer (Knudson 1971, 1985) has gained overwhelming support as germ-line and somatic mutations have been shown to activate the malignant potential of oncogenes and to inactivate the repressor function of tumor suppressor genes (Bishop 1991). The analysis of these tumor-specific mutations has yielded fundamental information on the mechanisms of carcinogenesis, but their etiology has remained poorly understood. There is no agreement in the estimation of the relative contribution of insults by genotoxic agents and of endogenous DNA replication errors to the genesis of these mutations in cancer (Ames and Gold 1990; Weinstein 1991). The concept that spontaneous errors in DNA replication may be fundamental in transformation was put forward (Loeb et al. 1974; Cairns 1975) in an attempt to explain the genomic instability of cancer cells (Schimke et al. 1986; Cheng and Loeb 1993). A defective DNA replication factor could enhance the error rate in the tumor cell variants continuously selected during tumor progression (Foulds 1954; Nowell 1976). However, a critical prediction of this hypothesis, an increased mutation frequency in tumor cells, remained elusive despite intensive efforts (Harris 1991; Loeb 1991). The importance of DNA replication and repair in transformation is demonstrated by the association of various biochemical defects in these processes with hereditary diseases that predispose to cancer (Cleaver 1967; Lindahl et al. 1991). The genes encoding factors involved in the DNA synthesis and error repair pathways are beginning to be isolated and characterized (Palombo et al. 1994; Tanaka and Wood 1994). A causal link between mutations in these factors and the origin of mutations in oncogenes and tumor suppressor genes is for the first time in sight. Colorectal cancer is one of the best-characterized examples of the multistage nature of carcinogenesis. A dominant oncogene, c-Ki-ras, and at least three distinct tumor suppressor genes, p53, DCC, and APC, are consistently involved in colorectal tumorigenesis (Fearon and Vogelstein 1990; Fearon and Jones 1992). In addition to the mutations in these critical genes, tumors of the colon and rectum contain other apparently random genetic alterations that exhibit a remarkably heterogeneous distribution in their extent (Vogelstein et al. 1989).DNA fingerprinting of hypervariable human minisatellite sequences is useful for the comparative analysis of multiple loci between different individuals (Jeffreys et al. 1985, 1990). DNA fingerprinting of minisatellite loci detected occasional somatic genetic alterations in gastrointestinal tumors (Thein et al. 1987; Armour et al. 1989; Vogelstein et al. 1989). The arbitrarily primed polymerase chain reaction (AP-PCR) is a DNA fingerprinting technique based in the amplification by PCR (Mullis and Faloona 1987) of multiple DNA fragments with the use of a single arbitrary primer (Welsh and McClelland 1990), The reproducible and quantitative amplification of many anonymous genomic sequences in a simple experiment permits the unbiased examination of the cell genome and provides a powerful tool for the analysis of the genetic alterations accompanying malignancy. DNA fingerprinting by AP-PCR disclosed the presence of ubiquitous somatic mutations (USM) at simple repeated sequences (SRS) in the genome of some colorectal tumors (Peinado et al. 1992). These USM at SRS unveiled a new mutator mechanism for oncogenesis, because they accumulate after the mutational unfolding of an acquired or inherited defect in the fidelity of DNA replication, ultimately underlying tumor formation (Ionov et al. 1993). Here we describe in …