van Houten V M, Tabor M P, van den Brekel M W, Denkers F, Wishaupt R G, Kummer J A, Snow G B, Brakenhoff R H
Department of Otolaryngology/Head and Neck Surgery, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Clin Cancer Res. 2000 Oct;6(10):3803-16.
The prognosis of cancer patients is determined by the radicalness of treatment: residual tumor cells will grow out and develop in manifest local recurrences, regional recurrences, and distant metastases. Classical diagnostic methods such as radiology and histopathology have limited sensitivities, and only by molecular techniques can minimal residual disease be detected. In tissue samples containing the normal tissue counterpart of a tumor, only tumor-specific markers can be exploited, whereas in other samples, tissue-specific markers can be used. At present, there are two main methodologies in use, one based on antigen-antibody interaction and the other based on amplified nucleic acids. The most commonly used nucleic acid markers are mutations or alterations in tumor DNA (tumor-specific markers) or differentially expressed mRNA (tissue-specific markers). Many reports and reviews have been published on the assessment of minimal residual disease by molecular markers, showing either positive or negative clinical correlations. One of the main reasons for these contradictory findings is the technical difficulty in finding the small numbers of tumor cells in the large number of normal cells, which necessitates sensitivities of the assays up to 1 tumor cell in 2 x 10(7) normal cells. These assays often are complex, demand considerable experience, and usually are laborious. In this review, we will address a number of the technical issues related to molecular assays for tumor cell detection that make use of nucleic acids as markers. Many difficulties in data interpretation are at least in part because of technical details that might have been solved by the incorporation of one or more appropriate controls. We hope that this review clarifies a number of these issues and help clinicians and investigators interested in this field to understand and weigh the contradictory findings in the published studies. This will help move the field forward and facilitate clinical implementation.
残留的肿瘤细胞会生长并发展为明显的局部复发、区域复发和远处转移。放射学和组织病理学等传统诊断方法的敏感性有限，只有通过分子技术才能检测到微小残留病灶。在含有肿瘤正常组织对应物的组织样本中，只能利用肿瘤特异性标志物，而在其他样本中，可以使用组织特异性标志物。目前，有两种主要的方法在使用，一种基于抗原-抗体相互作用，另一种基于核酸扩增。最常用的核酸标志物是肿瘤DNA中的突变或改变（肿瘤特异性标志物）或差异表达的mRNA（组织特异性标志物）。关于通过分子标志物评估微小残留病灶的许多报告和综述已经发表，显示出正或负的临床相关性。这些矛盾结果的主要原因之一是在大量正常细胞中找到少量肿瘤细胞存在技术困难，这需要检测方法的敏感性达到每2×10⁷个正常细胞中有1个肿瘤细胞。这些检测通常很复杂，需要相当多的经验，而且通常很费力。在这篇综述中，我们将探讨一些与利用核酸作为标志物进行肿瘤细胞检测的分子检测相关的技术问题。数据解释中的许多困难至少部分是由于技术细节造成的，而这些细节可能通过纳入一个或多个适当的对照来解决。我们希望这篇综述能澄清其中的一些问题，并帮助该领域感兴趣的临床医生和研究人员理解和权衡已发表研究中的矛盾结果。这将有助于推动该领域的发展并促进临床应用。
