A cancer DNA phenotype in healthy prostates, conserved in tumors and adjacent normal cells, implies a relationship to carcinogenesis

Abstract

A cancer DNA phenotype, identical to the DNA structure of tumors, has been identified in the prostate glands of certain healthy men over 55 years of age. We now show that the same DNA signature exists in normal tissues adjacent to tumors. This finding implies that the phenotype is maintained in normal prostate cells from its inception through tumor development. The presence of the phenotype in tumors, adjacent normal cells, and in the normal prostate cells of certain older men suggests that it is a potentially critical factor in tumor development and may serve as an early biomarker for cancer risk assessment. Intervention to inhibit the development of the phenotype in healthy men, or to eliminate it once formed, may suppress or even prevent tumor formation.cancer phenotype ͉ DNA structure ͉ cancer biomarkers ͉ cancer prediction and intervention ͉ Fourier transform-infrared spectroscopy U sing established Fourier transform-infrared (FT-IR) statistical models (1-5), we have demonstrated previously a cancer DNA phenotype in the limbs of mice 10 weeks after injecting the carcinogen 3-methylcholanthrene (4). This phenotype was identified in normal tissues 8 weeks before tumor formation. Strikingly, administration of the prodrug cyclophosphamide every 10 days after 3-methylcholanthrene injection delayed tumor formation by about 30% and almost completely suppressed development of the phenotype, thus suggesting that it may also be inhibited by other intervention strategies with less toxic side effects (4).In a previously reported study (2), a similar cancer DNA phenotype was identified in the prostate glands of certain healthy older men (55-80 years old). Both studies showed differences between the DNA of normal tissues and those tissues with the phenotype characterized by significant alterations in the base and backbone structures. In the prostate, for example, the development of the phenotype appeared to be age-related in that no evidence was found for it in men younger than 36 years of age. A statistical comparison of the FT-IR spectrum of the cancer phenotype with the DNA spectrum of normal prostate tissues of the healthy younger men revealed a broad array of differences in base structures (e.g., N-H and C-O), as well as in vertical base-stacking interactions. Various differences were also found in the phosphodiester-deoxyribose backbone (2). These differences likely arise from constituents in the microenvironment (e.g., reactive oxygen species) capable of inducing conformational changes in the backbone via disruptions in the planar base structure (6).The previous evidence (2) for a cancer DNA phenotype in certain older men suggests that this structure may respond differently in transcription and replication from the DNA of younger men, thus potentially increasing cancer risk. We now report that the cancer DNA phenotype in the prostate glands of older men is indistinguishable from the phenotype found in histologically normal tissues surrounding tumors. This finding implies that the phenotype is structurally stable, ...

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