A UNIFIED THEORY OF CARCINOGENESIS BASED ON ORDER-DISORDER TRANSITIONS IN DNA-STRUCTURE AS STUDIED IN THE HUMAN OVARY AND BREAST

Fourier transform-infrared/statistics models demonstrate that the mali gnant transformation of morphologically normal human ovarian and breas t tissues involves the creation of a high degree of structural modific ation (disorder) in DNA, before restoration of order in distant metast ases. Order-disorder transitions were revealed by methods including pr incipal components analysis of infrared spectra in which DNA samples w ere represented by points in two-dimensional space. Differences betwee n the geometric sizes of clusters of points and between their location s revealed the magnitude of the order-disorder transitions. Infrared s pectra provided evidence for the types of structural changes involved. Normal ovarian DNAs formed a tight cluster comparable to that of norm al human blood leukocytes. The DNAs of ovarian primary carcinomas, inc luding those that had given rise to metastases, had a high degree of d isorder, whereas the DNAs of distant metastases from ovarian carcinoma s 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 f emale breasts were substantially disordered (e.g., compared with the h uman blood leukocytes) as were those of the primary carcinomas, whethe r or not they had metastasized, The DNAs of distant breast cancer meta stases were relatively ordered. These findings evoke a unified theory of carcinogenesis in which the creation of disorder in the DNA structu re is an obligatory process followed by the selection of ordered, muta ted DNA forms that ultimately give rise to metastases.