Cancer-related changes in prostate DNA as men age and early identification of metastasis in primary prostate tumors

Abstract

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...

Facile Quantification of Lesions Derived from 2‘-Deoxyguanosine in DNA

“…Average adduct yield with 2 in 287 nt duplex DNA (2.5 pmol) as a function of 137 Cs dose. Circles, Na 2 IrCl 6 ; squares, K 3 Fe(CN) 6 .…”

“…Although both produced adducts with 2 in the presence of Na 2 IrBr 6 , only OxodG was trapped when K 3 Fe(CN) 6 was used as the oxidant (Figures 1 and 2). The selective biotinylation of DNA containing the lesions as a function of oxidant indicated that individual amounts of OxodG and Fapy•dG in randomly damaged DNA could be determined using 2 as part of a fluorescence assay (Scheme 1).…”

“…The amount of biotinylated DNA was measured as a function of dose using Na 2 IrCl 6 and K 3 Fe(CN) 6 as oxidants (Figure 3). The adduct yield varied linearly with dose when either oxidant was used.…”

A seemingly most effective target for early detection and intervention of prostate tumor invasion

“…These theories are consistent with experimental data from tissue cultures or animal models, but they are hard to reconcile with four critical facts: (a). previous studies have revealed that some healthy men between 19 and 29 years old demonstrated a spectrum of proliferative abnormalities in the prostate, including atypical hyperplasia, dysplasia, and incipient adenocarcinoma [11][12][13], (b) Recent studies have detected a DNA phenotype that is identical to the DNA structure of invasive prostate cancer in certain healthy men, and in normal prostate tissues adjacent to prostate cancer [14][15][16][17], (c) a majority of PIN express high le-vels of proteolytic enzymes, but only about 30% of untreated PIN progress to invasive lesions during patients' lifetime [18][19][20][21], and (d) results from worldwide human clinical trials with a wide variety of proteolytic enzyme specific inhibitors to treat or prevent tumor invasion have been very disappointing [22,23]. Together, these suggest that alternative mechanism(s) may exist for prostate tumor invasion.…”

Chemometrics of Cells and Tissues Using IR Spectroscopy - Relevance in Biomedical Research

“…Early works focused on defining the tissue variability in terms of IR spectra (Chiriboga et al 1998a,b,c, Wood et al 2004. This led to a large number of studies with different tissues and cell lines with an objective to make the technique relevant to oncology (Fukuyama et al 1999, Diem et al 2000, Gao et al 1999, Yano et al 2000, Malins et al 2003. The potential application in other biomedical fields was expanded by studying the classification of microorganisms using the technique and using it for identifying pathogens , Choosmith et al 2001, Sandt et al 2003, Essendoubi et al 2005.…”