Familial and Early Onset Colorectal Cancer

家族性和早发性结直肠癌 摘要 结直肠癌(CRC)是一种常见的、具有潜在致命性的疾病，通常发生在老年人身上。 一种零星的过程，主要与饮食和其他环境影响有关。然而，约4%的 CRC可归因于特定的遗传综合征，如Lynch综合征、家族性腺瘤 息肉病，以及其他一些罕见的疾病。另有20%-30%的结直肠癌患者有一级亲属 但尚不清楚这种熟悉性在多大程度上是由于共同的基因而不是共同的 环境因素。无论如何，我们几乎没有什么方法来识别这些高危人群。CRC是 由于可获得多种有效的筛查模式，因此特别适合于预防战略， 但我们不能频繁地对每个人进行筛查，如果这些资源得到利用，会更有效 在那些疾病风险最高的人中更密集，而在那些 一般或更低的风险。此外，大约5%-10%的结直肠癌发生在相对年轻、50岁和 即使是雄心勃勃的筛查建议对这些人来说也是不够的。 这个项目的目标是研究在家庭基础上患结直肠癌风险增加的个人，或者 非家族性早发性结直肠癌，以便为他们提供适当的强化筛查，以减轻他们的 有死于癌症的风险。应用的重点将是DNA错配修复(MMR)的改变。 基因。我们通过合作积累了大量常规和独特的CRC标本 寻找一些以前没有探索过的可能性。甲基化诱导的MLH1基因沉默 发生是由于其启动子中的CpG岛，约占CRCs的12%。我们已经开发出一种 在体外和体内研究MLH1基因甲基化调控的独特模型。我们将测试 假设我们实验室发现的一种独特的脱甲基剂可以在体外逆转这一过程，并 在活体内。我们还将寻找甲基化诱导MSH2和MSH6基因沉默的证据，这是 在它们的启动子中也有CpG岛，应该对同样的扰动敏感。我们会寻找 无家族病史患者早发性结直肠癌的发病机制 通过寻找启动子来测试一组新的微卫星标记的微卫星不稳定性(MSI) 这些肿瘤中的甲基化表型，并通过使用新的方法来寻找低水平的MSI。最后，我们会 测试低水平MSI是由MSH3基因下调引起的假设，并且这是 这一过程有助于在不断增长的肿瘤中产生高转移性克隆。 这个应用程序的广泛目标是开发其他工具，以提高我们更精确地 对CRC进行分类，以更准确地解释CRC中的突变签名，这将 允许我们为结直肠癌患者提供更高度个性化的治疗，特别是年轻或 有这种疾病的阳性家族史。

FAMILIAL AND EARLY ONSET COLORECTAL CANCER ABSTRACT Colorectal cancer (CRC) is a common and potentially lethal disease that usually occurs in older people, and is a sporadic process principally related to dietary and other environmental influences. However, about 4% of CRC can be attributed to specific genetic syndromes such as Lynch Syndrome, familial adenomatous polyposis, and a few other rare diseases. Another 20-30% of patients with CRC have a first degree relative with CRC, but it is not known how much of this familiality is due to shared genes rather than shared environmental factors. In any event, we have few methods of identifying these high-risk people. CRC is particularly suited to preventive strategies because of the availability of multiple effective screening modalities, but we cannot screen everyone frequently, and these resources would be more effective if they were used more intensively in those people at greatest risk for the disease, and more sparingly in those individuals at ordinary or lower risk. Also, about 5-10% of CRC occurs in people who are relatively young, <50 years old, and even ambitious screening recommendations are inadequate for these individuals. The goals of this project are to study individuals who are at increased risk for CRC on a familial basis, or for non-familial early-onset CRC, so that they might be offered appropriately intensive screening to mitigate their risk of dying of cancer. The focus of the application will be on alterations of the DNA mismatch repair (MMR) genes. We have used collaborations to accumulate a large number of routine and unique CRC specimens to look for a number of previously unexplored possibilities. Methylation-induced silencing of the MLH1 gene occurs because of a CpG island in its promoter, and accounts for about 12% of CRCs. We have developed a unique model to study the regulation of methylation of the MLH1 gene in vitro and in vivo. We will test the hypothesis that a unique demethylating agent discovered in our laboratory can reverse this process in vitro and in vivo. We will also look for evidence of methylation-induced silencing of the MSH2 and MSH6 genes, which also have CpG islands in their promoters, and should be susceptible to the same perturbation. We will look for mechanisms responsible for early-onset CRC in patients who do not appear to have a family history of this by testing a new panel of microsatellite markers for microsatellite instability (MSI), by looking for the promoter methylator phenotype in these tumors, and by using novel methods to look for low-level MSI. Finally, we will test the hypothesis that low-level MSI is caused by the down-regulation of the MSH3 gene, and that this process facilitates the generation of highly metastatic clones within a growing tumor mass. The broad aim of this application is to develop additional tools that increase our ability to more precisely categorize CRCs, to develop more accurate interpretations of the mutational signatures in CRCs, which will permit us to deliver more highly personalized treatment to CRC patients, particularly those who are young or have positive family histories of this disease.