Genomic instability is a molecular feature common to the progression of many cancers, particularly those that demonstrate genetic defects in mismatch repair (MMR) enzymes. The primary role of the MMR system is to maintain genomic stability by removing replication errors from DNA. This repair pathway was originally implicated in human cancer through an association between microsatellite instability (MSI) in colorectal tumors in hereditary nonpolyposis colon cancer (HNPCC). Microsatellites are ubiquitous short tandem-repeat sequences widely and randomly distributed throughout the human genome. They are acutely prone to replication errors that result in expansions and contractions of the repeat unit due to misalignment of the template and daughter strands. A number of human genes associated with cancer contain microsatellite repeats within the coding and non-coding regions of the transcribed sequences. It has been suggested that instability of repeat sequences in the coding regions of several of these genes, plays a role in the progression of disease, presumably by gene inactivation through the introduction of frameshift mutations. Variability of microsatellite repeat lengths in non-coding regions of transcripts has also been implicated in the regulation of gene expression. We hypothesize that the genes in the molecular pathway(s) of cancer progression are subject to gene regulation by microsatellite repeat sequence variability, and that the accumulation of these variants through defects in MMR or the normal aging process contribute to cancer progression by influencing gene expression and chromatin remodeling as it relates to the positioning of regulatory elements, mRNA stability and methylation status of CpG islands. The completion of the human genome sequence offers the opportunity to screen for and evaluate the role of these simple sequence repeats in genome maintenance and gene expression. Ultimately, we will advance a specific mission of the NCI: to gain a more complete understanding of genetic and epigenetic determinants of cancer and the biological mechanisms underlying cancer initiation and progression. To achieve these goals our research aims are to (1) evaluate and correlate repeat variability with cancer-associated changes in colorectal cell lines, (2) examine and correlate methylation status of CpG islands with repeat variability and replication error (RER) classification and (3) assay gene expression and activity levels in genes demonstrating microsatellite variability. The results of these studies should contribute to our current understanding of cancer, identify molecular markers of cancer progression and will shed light on atypical modulators of gene expression. /
TO PUBLIC HEALTH: The overall goal of this study is to investigate the hypothesis that the genes in the molecular pathway(s) of cancer progression are subject to transcriptional regulation by microsatellite repeat sequence variability. Ultimately, we will advance a specific mission of the NCI: to gain a more complete understanding of genetic and epigenetic determinants of cancer and the biological mechanisms underlying cancer initiation and progression. ? ? ?
