Familial and Early Onset Colorectal Cancer

家族性和早发性大肠癌 摘要 结直肠癌（CRC）是一种常见的潜在致命疾病，通常发生在老年人中， 主要与饮食和其他环境影响有关的偶发过程。然而，大约4%的 CRC可归因于特定的遗传综合征，例如林奇综合征、家族性腺瘤性结肠癌、结肠癌性直肠癌和结肠癌性直肠癌。 息肉病和其他一些罕见的疾病。另外20-30%的CRC患者有一级亲属 与CRC，但它是不知道有多少这种熟悉是由于共同的基因，而不是共享 环境因素在任何情况下，我们都没有什么方法来识别这些高危人群。CRC是 特别适合预防策略，因为有多种有效的筛查方式， 但我们不可能经常对每个人进行筛查，如果这些资源得到利用， 在那些疾病风险最大的人群中更密集，而在那些 普通或低风险。此外，约5-10%的CRC发生在相对年轻的人中，<50岁， 即使是雄心勃勃的筛查建议对这些人来说也是不够的。 该项目的目标是研究在家庭基础上CRC风险增加的个体，或 非家族性早发性CRC，以便为他们提供适当的强化筛查，以减轻他们的 死于癌症的风险。该应用程序的重点将是改变DNA错配修复（MMR） 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MLH 1基因沉默 由于其启动子中的CpG岛而发生，约占CRCs的12%。我们已经开发出一种 这是一个独特的模型，用于研究MLH 1基因在体外和体内的甲基化调控。我们将测试 假设我们实验室发现的一种独特的去甲基化剂可以在体外逆转这一过程， in vivo.我们还将寻找甲基化诱导的MSH 2和MSH 6基因沉默的证据， 在它们的启动子中也有CpG岛，并且应该对相同的扰动敏感。我们将寻找 在似乎没有家族史的患者中， 通过寻找启动子，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。最后我们将 检验低水平MSI是由MSH 3基因下调引起的假设， 这一过程有助于在生长的肿瘤块内产生高转移性克隆。 这个应用程序的主要目标是开发额外的工具，以提高我们的能力，更精确地 对CRCs进行分类，以更准确地解释CRCs中的突变特征， 允许我们为CRC患者提供更高度个性化的治疗，特别是那些年轻或 有这种疾病的家族史。

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.