HISTOLOGIC AND MOLECULAR CHANGES IN UC TUMORIGENESIS

本研究的长期目标是更好地了解慢性广泛性溃疡性结肠炎（UC）肿瘤进展的分子机制，并将这些知识用于UC的癌症预防。我们之前的研究表明，通过DNA非整倍体的存在检测到的染色体不稳定性（CIN）是组织学进展为不典型增生或癌症的危险因素。最近，我们发现荧光原位杂交（FISH）是一种更敏感的CIN指标：这种方法能够在局灶性发育不良或癌症患者的整个结肠中检测到染色体不稳定的证据。我们认为CIN反映了UC中导致癌症风险的潜在过程。在我们的具体目标1中，我们将确定UC中CIN的原因和模式，测试其与DNA损伤升高或端粒缩短有关的假设。在特定目标2中，我们将确定饮食干预是否可以影响CIN水平，这是由特定目标1中衍生的标记物确定的。具体来说，我们提出了两项双盲、安慰剂对照、前瞻性先导干预研究：1)在组织学不明确的UC患者中使用叶酸；2)在结肠轻度不典型增生的UC患者中使用熊去氧胆酸。我们将在干预前后检测染色体不稳定性。如果我们关于CIN可以作为发育不良的早期标志的假设是正确的，它可能使临床医生进行一些直肠活检，确定那些肿瘤进展风险最大的患者，并将结肠镜监测工作集中在他们身上。此外，这些知识可以帮助为癌症预防策略的发展提供基础。

The long term objectives of this research are to develop a better understanding of the molecular mechanisms of neoplastic progression in chronic extensive ulcerative colitis (UC) and to use this knowledge for the prevention of cancer in UC. Our previous studies have indicated that chromosomal instability (CIN), detected by the presence of DNA aneuploidy, is a risk factor for the histologic progression to dysplasia or cancer. Recently, we have found that fluorescence in situ hybridization (FISH) is a more sensitive indicator of CIN: this method is able to detect evidence of chromosomal instability throughout the colon of patients with focal dysplasia or cancer. We believe that CIN is a reflection of the underlying process that contributes to cancer risk in UC. In our specific aim 1, we will determine the causes and patterns of CIN in UC, testing the hypotheses that it is related to elevated DNA damage or shortening of telomeres. In specific aim 2, we will determine whether dietary interventions can influence the levels of CIN as determined by markers derived from specific aim 1. Specifically, we propose two double-blind, placebo controlled, prospective pilot intervention studies: 1) using folate in UC patients with indefinite histology for dysplasia and 2) using ursodeoxycholic acid in UC patients with low-grade dysplasia in their colons. We will test for chromosomal instability pre and post intervention. If our hypothesis that CIN can be exploited as an early marker of dysplasia is correct, it might enable clinicians to take a few rectal biopsies, determine those patients who are at greatest risk for neoplastic progression and concentrate colonoscopic surveillance efforts on them. Moreover, this knowledge could help provide the underpinnings for development of cancer prevention strategies.