Weinberg R A
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cancer Surv. 1995;25:3-12.
A number of distinct strategies have been used over the past two decades to uncover the genes involved in tumorigenesis. Their use raises the questions of whether we will require novel approaches in order to continue the progress of cancer genetics. Retrovirus mediated transduction of proto-oncogenes and transfection of tumour associated oncogenes are both inefficient ways of uncovering oncogenes, each being encumbered by technical obstacles that limit their utility. Improvements in the gene transfer strategy may yield a host of new oncogenes. New cloning techniques may have a role here as well as in revealing the existence of genes that are amplified in tumour cell genomes. The major technique for uncovering novel tumour suppressor genes--detection of loss of heterozygosity--is also limited in its sensitivity to detecting genes that are lost in large numbers of tumours. The techniques for uncovering these genes through analysis of pedigrees in which mutant versions of these genes are passed through the germline are encumbered by issues of penetrance and the complexities associated with the inheritance of polygenic traits. In both instances, improvements in data acquisition and analysis will reveal tumour suppressor genes that have proved elusive until now. Over the next decade, we will learn much about how the defects in another apparatus--that responsible for the maintenance of genomic integrity--contribute to cancer susceptibility. Beyond these genes lie yet others about which we seem to know little at present--those that induce the last stages of cancer including invasiveness and metastasis. These will represent an entirely new cohort of genes to be uncovered over the next decade.
在过去二十年中，人们采用了多种不同的策略来发现参与肿瘤发生的基因。这些策略的应用引发了这样的问题：为了继续推动癌症遗传学的发展，我们是否需要新的方法。逆转录病毒介导的原癌基因转导和肿瘤相关癌基因的转染都是发现癌基因的低效方法，每种方法都受到技术障碍的限制，这些障碍限制了它们的实用性。基因转移策略的改进可能会产生许多新的癌基因。新的克隆技术在发现肿瘤细胞基因组中扩增的基因的存在方面可能也会发挥作用。发现新型肿瘤抑制基因的主要技术——杂合性缺失检测——在检测大量肿瘤中缺失的基因时，其灵敏度也受到限制。通过分析这些基因的突变版本通过种系传递的家系来发现这些基因的技术，受到外显率问题以及与多基因性状遗传相关的复杂性的困扰。在这两种情况下，数据采集和分析的改进将揭示迄今难以捉摸的肿瘤抑制基因。在未来十年，我们将更多地了解另一种机制——负责维持基因组完整性的机制——中的缺陷如何导致癌症易感性。除了这些基因之外，还有其他一些基因，我们目前似乎对它们知之甚少——那些诱导癌症最后阶段（包括侵袭和转移）的基因。这些将代表未来十年有待发现的全新一批基因。
