Sankaranarayanan K, Chakraborty R
Department of Radiation Genetics & Chemical Mutagenesis, Sylvius Laboratories, University of Leiden, The Netherlands.
Radiat Res. 1995 Aug;143(2):121-43.
This paper presents an overview of current knowledge on genetic predisposition to cancer and on enhanced sensitivity of cancer-predisposed genotypes to cancers induced by ionizing radiation. It is intended to provide a background and set the stage for the next papers in this series in which we will assess how such heterogeneity (with respect to predisposition to cancer and presence of radiosensitivity genotypes) in a population may affect estimates of the risk of radiation-induced cancers. The main findings and/or conclusions of the present paper are the following: (1) "Cancer-predisposing genes" (i.e. those at which germinal mutations predispose to cancer) are present in the human genome; these genes are responsible not only for the rare familial cancer syndromes but also for a proportion of the common cancers. At least 21 such genes have now been cloned (including 9 tumor suppressor genes, 11 DNA repair genes and 1 proto-oncogene); further, at least 8 putative tumor suppressor genes and a gene involved in ataxia telangiectasia have been localized to specific chromosomes. (2) These genes play crucial roles in the control of cellular proliferation, programmed cell death (apoptosis) and/or one or another DNA repair pathway. Consequently, mutations in these genes are likely to "liberate" the cells from the normal constraints imposed by them, resulting in unconstrained growth characteristic of cancer. (3) At present, the evidence for increased sensitivity of cancer-predisposed genotypes to radiation-induced cancers is limited. However, current knowledge of the known functions of the cancer-predisposing genes and of the consequences of mutations in these provide (a) sufficient grounds for assuming that the genotypes of those predisposed to cancer may be at an increased risk for radiation-induced cancers and (b) the rationale for attempts to estimate quantitatively the impact of genotype-dependent differences in cancer predisposition and radiosensitivity on cancer risks in an irradiated population.
本文概述了目前关于癌症遗传易感性以及癌症易感基因型对电离辐射诱发癌症的增强敏感性的知识。其目的是为该系列的下一篇论文提供背景并奠定基础，在后续论文中我们将评估人群中的这种异质性（关于癌症易感性和放射敏感性基因型的存在）如何影响辐射诱发癌症风险的估计。本文的主要发现和/或结论如下：（1）人类基因组中存在“癌症易感基因”（即那些生殖细胞突变易患癌症的基因）；这些基因不仅导致罕见的家族性癌症综合征，也导致一部分常见癌症。目前至少已克隆出21个这样的基因（包括9个肿瘤抑制基因、11个DNA修复基因和1个原癌基因）；此外，至少8个推定的肿瘤抑制基因和一个与共济失调毛细血管扩张相关的基因已定位到特定染色体上。（2）这些基因在控制细胞增殖、程序性细胞死亡（凋亡）和/或一种或另一种DNA修复途径中起关键作用。因此，这些基因中的突变可能使细胞从它们施加的正常限制中“解放”出来，导致癌症特有的不受限制的生长。（3）目前，癌症易感基因型对辐射诱发癌症敏感性增加的证据有限。然而，目前对癌症易感基因已知功能及其突变后果的了解提供了：（a）充分理由假设癌症易感者的基因型可能增加辐射诱发癌症的风险；（b）定量估计癌症易感性和放射敏感性的基因型依赖性差异对受辐照人群癌症风险影响的理论依据。
