A unified theory of carcinogenesis based on order–disorder transitions in DNA structure as studied in the human ovary and breast

Abstract

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...

Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand

“…In an attempt to answer this question, we used Fourier transform-infrared (FT-IR) spectroscopy with multivariate statistics to delineate structural differences between thin films of a 25-base DNA strand and comparable strands containing centrally located single G o and A o groups. FT-IR͞statistical analysis was previously used to study subtle changes in base and phospho-deoxyribose structures of DNA in relation to tumor progression (13)(14)(15)(16)(17)(18)(19). In the present study, a number of spectral differences attributable to base interactions and backbone conformations were identified between the 25-base parent strand and derivatives containing G o and A o substituents.…”

“…In this regard, FT-IR spectroscopy with multivariate statistics is known to be sensitive to subtle changes in the base and backbone structures of DNA in cancer-prone tissues and neoplasms [e.g., prostate (15) and breast (14,18,19)]. The FT-IR͞statistical approach is thus an attractive means for acquiring information on conformational and other changes in a variety of synthetic and natural DNA structures (17).…”

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

“…The Spearman correlation coefficients between base lesion concentrations and age were 0.52 (P ϭ 0.015) for 8-OH-Gua, 0.55 (P ϭ 0.01) for 8-OH-Ade, and 0.50 (P ϭ 0.02) for FapyGua. In a previous study (32), increased variance in mutagenic base lesions in tumor-prone tissues was hypothesized to be an obligatory precursor to clonal selection and subsequent tumor formation.…”

Development of a cancer DNA phenotype prior to tumor formation

“…Results and Discussion MCA-Induced DNA Damage Before Tumor Formation. We have demonstrated that the FTIR statistical models of DNA used in this study are capable of identifying a variety of subtle changes in base functional group and backbone structures as well as alterations in conformational properties (20) associated with carcinogenesis (19,21,(23)(24)(25). Specifically, this technology has been used most recently to discriminate between DNA structures of normal prostate tissues, primary tumors, metastasizing primary tumors, and distant metastases of the prostate (18).…”

“…7, we investigated changes in DNA structure associated with MCA exposure. Fourier transforminfrared (FTIR) spectral models (17)(18)(19)(20)(21) were used to identify alterations in the nucleotide bases and phosphodiesterdeoxyribose backbone during tumorigenesis. Moreover, we looked for the early development of a DNA structure (cancer DNA phenotype), indistinguishable from that of tumor DNA, which was found in the prostates of older, cancer-free men (18).…”