Using statistical analyses of Fourier transform-IR spectra, we show that DNA of the histologically normal prostates of men 16 -80 years old undergoes structural changes in the bases and backbone with increasing age. Of the older men (ages 55-80), 42% exhibited a DNA phenotype mimicking that of primary prostate tumors from a comparable age group. This cancer-like phenotype, which was not found in the younger men (ages 16 -36), appears to arise from progressive age-related damage to DNA. The mean concentrations of 8-hydroxypurine lesions (e.g., 8-hydroxyguanine) were substantially higher for the older men than for the younger men. This finding suggests that the hydroxyl radical contributed to the structural changes that characterize the cancer-like phenotype. Strikingly, we were additionally able to discriminate between the DNA of primary prostate tumors and the DNA of primary prostate tumors from which distant metastases had been identified. Moreover, logistic regression analysis was able to predict the probability that a tumor had metastasized with Ϸ90% sensitivity and specificity. Collectively, these findings are particularly promising for identifying men at risk for developing prostate cancer, as well as for the early determination of whether a primary tumor has progressed to the metastatic state. This is highly important because the prognosis of histologically similar prostate carcinomas varies, thus creating a need to predict which cancers are most likely metastatic.I n the United States, prostate cancer is the most prevalent of all cancers and the second-leading cause of cancer mortality in men (1). The incidence rates for this disease rise markedly as a function of increasing age (1-3). Notably, 70% of all newly diagnosed prostate cancers occur in men over age 65 (2). The greatest threat from prostate cancer lies in its potential to metastasize (3). Clinical diagnosis of metastatic prostate cancer presently depends on histological identification of distant metastases. Yet, by the time the tumor has metastasized, the success of intervention is severely limited. Clearly, there is a need to identify early subcellular changes in the prostate, such as in DNA, associated with aging, primary tumor development, and the progression to metastasis.We have reported (4) that the ratio of mutagenic 8-hydroxy to putatively nonmutagenic ring-opened purine lesions in prostate DNA increased Ϸ3-fold in men between the ages of 16 and 83. In addition, a related study (5) showed a substantial accumulation of 8-hydroxyguanine (8-OH-Gua) in the liver, kidney, and intestine as rats aged. It was later reported (6) that levels of this base lesion increased 186% in the livers of rats between 5 and 30 months. Several factors have been suggested to explain agerelated increases in DNA base lesion concentrations in various tissues, among them reduced enzyme repair (7-10), a slow loss of DNA nuclease activity (5), and an increase in base oxidation (11). These findings focus attention on the importance of age-related free radical damage to...