Models of granulocyte DNA structure are highly predictive of myelodysplastic syndrome

Abstract

We have used statistical models based on Fourier transforminfrared spectra to differentiate between the DNA structure of normal granulocytes and those obtained from patients with myelodysplastic syndrome (MDS). The substantial degree of discrimination achieved between the two DNA groups is attributed to differences in the nucleotide base and backbone structures. These structural differences allowed for the development of a discriminant analysis model that predicted, with high sensitivity and specificity, which DNA came from normal granulocytes vs. granulocytes from MDS patients. The findings are a promising basis for developing a blood test to diagnose and predict the occurrence of MDS, for which there is currently a paucity of molecular markers.clonal blood disease ͉ blood test ͉ disease diagnosis and prediction ͉ Fourier transform-infrared spectroscopy M yelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by peripheral blood cytopenias caused by ineffective hematopoiesis that can lead to bone marrow failure (1). It is estimated that 15,000 to 20,000 cases of MDS are diagnosed each year in the United States, primarily in patients over 60 years of age (2, 3), most of whom die of infection or bleeding. Moreover, up to 40% of cases transform to acute myelogenous leukemia (2, 4). Only half of MDS cases are characterized by nonrandom chromosomal abnormalities, and for the rest diagnosis is largely dependent on the presence of blood count suppression in association with morphologic abnormalities of both mature and immature myeloid cells (5, 6). As a consequence of this phenotypic mimicry, the distinction between MDS and nonclonal disorders causing bone marrow failure is often difficult.Although the molecular basis of MDS remains to be clarified, it is recognized that aberrant DNA hypermethylation is one event implicated in the transformation of MDS to acute myelogenous leukemia (7-9). This reaction, which is catalyzed by DNA methyltransferase enzymes (10), has been shown to favor promoter-associated CpG-rich regions (CpG islands) of the DNA (8, 11-13). The methylation of cytosine and certain other epigenetic events (e.g., reactions of oxygen free radicals; ref. 14) leading to base modifications would be expected to interfere with the normal vertical base stacking properties of DNA, which, in turn, would induce conformational changes in the phosphodiester-deoxyribose backbone (15, 16). These structural alterations are likely to affect the fidelity of DNA replication and transcription (17,18).We previously have demonstrated that highly sensitive statistical models of Fourier transform-infrared (FT-IR) spectra are capable of identifying subtle differences in the base and backbone structures of DNA in normal and abnormal tissues. This technology has been used successfully to discriminate between DNA structures of the normal and cancerous breast (19-23) and prostate (24,25). The structural differences were the basis for constructing statistical models that predict the probability of ca...

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

“…Structural assignments for spectral differences were based on previous reports (11 -13). The FT-IR statistical models have a high sensitivity for identifying differences between groups of DNA (1,3), as demonstrated by the ability to readily distinguish a 25-base oligonucleotide with a single 8-oxo substituent (6).…”

“…tical models (1)(2)(3)(4)(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.…”

Oxidative Changes in the DNA of Stroma and Epithelium from the Female Breast: Potential Implications for Breast Cancer

“…The DNA samples were also grouped by lesion concentrations, which revealed an uneven distribution of age relative to increasing values. In addition, we used Fourier transform-infrared (FT-IR) spectroscopy 5,[20][21][22] to delineate structural differences in the stromal DNA in relation to the various age groups and to determine whether such differences exist between the matched cell types.…”

Development of a cancer DNA phenotype prior to tumor formation

“…We also investigated whether the delay in MCA-induced tumor formation after systemic treatment with CPA is reflected in a delayed appearance of the cancer phenotype. We have used FTIR spectral models for predicting primary tumor formation and metastasis in the human breast (22) and prostate (18) and for the early diagnosis of the clonal hematopoietic stem-cell disorder, myelodysplastic syndrome (17).…”

“…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).…”