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Fourier transform-infrared͞statistics 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.The hydroxyl radical ( ⅐ OH) is a highly reactive chemical species that is known to alter the structure of DNA in human tissues (1-4). In hormone responsive tissues (e.g., the human breast), this radical is believed to be produced via the metal (e.g., Fe 2ϩ )-catalyzed decomposition of H 2 O 2 , which may arise from redox cycling of catecholestrogen metabolites (5) and xenobiotics (e.g., aromatic hydrocarbons) (6, 7). The ⅐ OH-induced modification of DNA involves the nucleotide base and phosphodiester-deoxyribose structures (3,8). The reaction rate with the bases has been estimated to be approximately four times that occurring with deoxyribose (8). The base reactions produce mutagenic derivatives, such as 8-hydroxyguanine (8-OH-Gua) and 8-hydroxyadenine (8-OH-Ade), together with the putatively nonmutagenic ring-opened structures 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-G) and 4,6-diamino-5-formamidopyrimidine (Fapy-A) (2, 9). The ⅐ OH also abstracts hydrogen atoms from the furanose ring of deoxyribose (8), which produces a variety of hydroxy derivatives that lead to strand breaks and the loss of phosphoric acid (8). Accordingly, the attack of the ⅐ OH creates substantial disorder likely reflected in the formation of potentially billions of new DNA structures (10), some of which may give rise to altered protein expression and function.Fourier transform-infrared (FT...