Malins D C, Polissar N L, Schaefer S, Su Y, Vinson M
Molecular Epidemiology Program, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA.
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7637-42. doi: 10.1073/pnas.95.13.7637.
Fourier transform-infrared/statistics models demonstrate that the malignant transformation of morphologically normal human ovarian and breast tissues involves the creation of a high degree of structural modification (disorder) in DNA, before restoration of order in distant metastases. Order-disorder transitions were revealed by methods including principal components analysis of infrared spectra in which DNA samples were represented by points in two-dimensional space. Differences between the geometric sizes of clusters of points and between their locations revealed the magnitude of the order-disorder transitions. Infrared spectra provided evidence for the types of structural changes involved. Normal ovarian DNAs formed a tight cluster comparable to that of normal human blood leukocytes. The DNAs of ovarian primary carcinomas, including those that had given rise to metastases, had a high degree of disorder, whereas the DNAs of distant metastases from ovarian carcinomas were relatively ordered. However, the spectra of the metastases were more diverse than those of normal ovarian DNAs in regions assigned to base vibrations, implying increased genetic changes. DNAs of normal female breasts were substantially disordered (e.g., compared with the human blood leukocytes) as were those of the primary carcinomas, whether or not they had metastasized. The DNAs of distant breast cancer metastases were relatively ordered. These findings evoke a unified theory of carcinogenesis in which the creation of disorder in the DNA structure is an obligatory process followed by the selection of ordered, mutated DNA forms that ultimately give rise to metastases.
傅里叶变换红外光谱/统计模型表明，形态学上正常的人类卵巢和乳腺组织的恶性转化涉及DNA中高度结构修饰（无序）的产生，随后远处转移灶中才恢复有序。通过包括对红外光谱进行主成分分析在内的方法揭示了有序-无序转变，其中DNA样本由二维空间中的点表示。点簇的几何尺寸及其位置之间的差异揭示了有序-无序转变的程度。红外光谱为所涉及的结构变化类型提供了证据。正常卵巢DNA形成了一个紧密的簇，类似于正常人血白细胞的簇。卵巢原发性癌的DNA，包括那些已发生转移的癌的DNA，具有高度的无序性，而卵巢癌远处转移灶的DNA则相对有序。然而，在分配给碱基振动的区域中，转移灶的光谱比正常卵巢DNA的光谱更多样化，这意味着遗传变化增加。正常女性乳腺的DNA与原发性癌的DNA一样，无论是否发生转移，都有显著的无序性。乳腺癌远处转移灶的DNA相对有序。这些发现引出了一种统一的致癌理论，即DNA结构中无序的产生是一个必然过程，随后是对有序的、突变的DNA形式的选择，最终导致转移。
