Anderson M W, Reynolds S H, You M, Maronpot R M
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Environ Health Perspect. 1992 Nov;98:13-24. doi: 10.1289/ehp.929813.
The accumulation of genetic damage in the forms of activated proto-oncogenes and inactivated tumor-suppressor genes is the driving force in the evolution of a normal cell to a malignant cell. For example, both the activation of ras oncogenes and the inactivation of several suppressor genes, including p53, have been observed in the development of human colon and lung tumors. Point mutations in key codons can activate ras proto-oncogenes and inactivate the p53 suppressor gene. Thus, several critical genes for tumorigenesis are potential targets for carcinogens and radiation that can induce point mutations at low doses. The ras proto-oncogenes are targets for many genotoxic carcinogens. Activation of the ras gene is an early event--probably the "initiating" step--in the development of many chemical-induced rodent tumors. ras Oncogenes are observed in more human tumors and at a higher frequency than any other oncogene, and activation of the proto-oncogene may occur at various stages of the carcinogenic process. Numerous proto-oncogenes other than the ras genes have been shown to be activated in human tumors and to a lesser extent in rodent tumors. Mechanisms that induce aberrant expression of proto-oncogenes are gene amplification and chromosomal translocation or gene rearrangement. Amplification of proto-oncogenes and possibly gene overexpression during the absence of gene amplification occur in the development of many human tumors. For a specific tumor type, amplification of any one proto-oncogene may occur at a low frequency, but the frequency of tumors in which at least one proto-oncogene is amplified can be much higher. Proto-oncogene amplification is usually associated with late stages of tumor progression; however, amplified HER2/neu has been observed in early clinical stages of mammary neoplasia. Activation of proto-oncogenes by chromosomal translocation has been detected at a high frequency in several hematopoietic tumors. Non-ras genes have been detected by DNA transfection assays in both human and rodent tumors. For example, ret and trk genes were found to be activated by gene rearrangements in human papillary thyroid carcinomas. Several potentially new types of oncogenes have also been detected by DNA transfection assays. The etiology of the genetic alterations observed in most human tumors is unclear at present. Examples of ras gene activation and those documented for mutations in the p53 gene demonstrate that exogenous conditions can induce oncogenic mutants of normal genes. The genetic alterations observed in most human tumors are probably generated by both spontaneous events and exogenous conditions.
以激活的原癌基因和失活的肿瘤抑制基因形式存在的遗传损伤积累，是正常细胞演变为恶性细胞的驱动力。例如，在人类结肠癌和肺癌的发生过程中，已观察到ras原癌基因的激活以及包括p53在内的几种抑制基因的失活。关键密码子中的点突变可激活ras原癌基因并使p53抑制基因失活。因此，几个肿瘤发生的关键基因是致癌物和辐射的潜在靶点，它们可在低剂量下诱导点突变。ras原癌基因是许多遗传毒性致癌物的靶点。ras基因的激活是许多化学诱导的啮齿动物肿瘤发生过程中的早期事件——可能是“启动”步骤。在更多的人类肿瘤中观察到ras癌基因，其频率高于任何其他癌基因，并且原癌基因的激活可能发生在致癌过程的各个阶段。除ras基因外，许多其他原癌基因已被证明在人类肿瘤中被激活，在啮齿动物肿瘤中激活程度较低。诱导原癌基因异常表达的机制是基因扩增和染色体易位或基因重排。在许多人类肿瘤的发生过程中，会出现原癌基因的扩增以及在无基因扩增情况下可能出现的基因过表达。对于特定的肿瘤类型，任何一个原癌基因的扩增可能以低频率发生，但至少有一个原癌基因被扩增的肿瘤频率可能会高得多。原癌基因扩增通常与肿瘤进展的晚期阶段相关；然而，在乳腺肿瘤形成的临床早期阶段已观察到HER2/neu基因的扩增。在几种造血系统肿瘤中，通过染色体易位激活原癌基因的频率很高。在人类和啮齿动物肿瘤中，通过DNA转染试验检测到了非ras基因。例如，在人类甲状腺乳头状癌中发现ret和trk基因通过基因重排被激活。通过DNA转染试验还检测到了几种潜在的新型癌基因。目前，大多数人类肿瘤中观察到的基因改变的病因尚不清楚。ras基因激活的例子以及p53基因突变的记录表明，外源性条件可诱导正常基因的致癌突变体。大多数人类肿瘤中观察到的基因改变可能是由自发事件和外源性条件共同产生的。
