Microsatellite variability within transcribed regions of genes involved in cancer

描述（由申请人提供）：基因组不稳定性是许多癌症进展的共同分子特征，特别是那些表现出错配修复（MMR）酶遗传缺陷的癌症。MMR系统的主要作用是通过去除DNA中的复制错误来维持基因组的稳定性。这种修复途径最初是通过与遗传性非息肉性结肠癌（HNPCC）结直肠肿瘤的微卫星不稳定性（MSI）相关而涉及人类癌症的。微卫星是普遍存在的短串联重复序列，广泛而随机地分布在人类基因组中。它们非常容易发生复制错误，由于模板和子链的错位导致重复单元的扩张和收缩。许多与癌症相关的人类基因在转录序列的编码区和非编码区都含有微卫星重复序列。有研究表明，这些基因编码区重复序列的不稳定性在疾病的进展中起作用，可能是通过引入移码突变导致基因失活。转录本非编码区微卫星重复长度的变异也与基因表达的调控有关。我们假设，癌症进展分子通路中的基因受微卫星重复序列变异性的基因调控，这些变异通过MMR缺陷或正常衰老过程的积累，通过影响基因表达和染色质重塑来促进癌症进展，因为它与调控元件的定位、mRNA稳定性和CpG岛的甲基化状态有关。人类基因组序列的完成为筛选和评估这些简单序列重复序列在基因组维持和基因表达中的作用提供了机会。最终，我们将推进NCI的一项具体任务：更全面地了解癌症的遗传和表观遗传决定因素以及癌症发生和发展的生物学机制。为了实现这些目标，我们的研究目标是：(1)评估重复变异性与结直肠癌细胞系癌症相关变化的相关性，(2)检查CpG岛的甲基化状态与重复变异性和复制错误（RER）分类的相关性，以及(3)测定显示微卫星变异性的基因的基因表达和活性水平。这些研究的结果将有助于我们目前对癌症的理解，确定癌症进展的分子标记，并将阐明基因表达的非典型调节剂。/与公共卫生相关：本研究的总体目标是调查癌症进展分子途径中的基因受微卫星重复序列变异性转录调控的假设。最终，我们将推进NCI的一项具体任务：更全面地了解癌症的遗传和表观遗传决定因素以及癌症发生和发展的生物学机制。

DESCRIPTION (provided by applicant): 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. / RELEVANCE 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.