DNA rearrangements, DNA methylation, and cancer
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Description
Epigenetic changes, especially, alterations in DNA methylation, are found in many types of human cancers. Aberrations in DNA methylation contribute to carcinogenesis by different mechanisms, such as, regulating tumor-associated gene expression and increasing the rates of point mutations. However, the possible association between the cancer-promoting DNA rearrangements and DNA methylation is unclear. Cytogenetic studies have revealed that chromosome 1 (Chr1) rearrangements are one type of the most common genetic abnormalities in a variety of human cancers. These rearrangements often involve the vicinity of the centromere of Chr1. Through studying Wilms' tumor, we provide the first piece of evidence that DNA hypomethylation in the pericentromeric satellite DNA of Chr1 may participate in this nonrandom chromosomal rearrangement in this type of cancer. Concerning the importance of DNA hypomethylation to carcinogenesis, we tried to establish a model system to detect DNA demethylation induced by chemicals. After studying several viral transcription control regions, the simian virus 40 early promoter and enhancer (SV40 early P/E) was found to be capable of overcoming the inhibitory effects of DNA methylation on gene expression in stable transfectants. Genomic sequencing analysis suggested that the Sp1 site-rich SV40 early promoter region is associated with the regional DNA demethylation, which could help turn on DNA methylation-silenced gene expression. In a double selection marker system, a DNA methyltransferase inhibitor, 5-azacytidine, was effective at reversing the inhibitory effects of DNA methylation but only when the initial level of DNA methylation was low Another assay system was developed to detect chromosome rearrangement-provoking carcinogens because the ability of genotoxic chemicals to cause chromosomal rearrangements has been little studied in terms of chemical carcinogenesis. Although our assay system involving activation of a promoter-deficient gene was not able to detect such rearrangements, it has advanced our understanding of promoter function. Lastly, a cancer-related chromosomal translocation, BCL-2/JH translocation, was found in the peripheral blood from almost half of healthy blood donors by a sensitive polymerase chain reaction (PCR) analysis. We have improved methods for isolating more blood DNA samples from a variety of cancer patients for this analysis in order to explore the association between the levels of this cancer-associated translocation and carcinogenesis in humans. These and above studies have helped elucidate the relationships between DNA methylation, DNA rearrangements, gene expression, and carcinogenesis