Familial and Early Onset Colorectal Cancer

描述（由申请人提供）：结直肠癌（CRC）是一种常见的潜在致死性疾病，通常发生在老年人中，是一种主要与饮食和其他环境影响有关的散发性过程。然而，约4%的CRC可归因于特定的遗传综合征，如Lynch综合征，家族性腺瘤性息肉病和其他一些罕见疾病。另外20-30%的CRC患者与CRC有一级亲属关系，但尚不清楚这种亲密关系有多少是由于共享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特别适合于预防策略，因为有多种有效的筛查方式，但我们不能经常筛查每个人，如果这些资源更密集地用于疾病风险最高的人群，而更谨慎地用于普通或较低风险的人群，这些资源将更有效。此外，大约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也不适合这些人。该项目的目标是研究在家族基础上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，以减轻他们死于癌症的风险。申请的重点将是DNA错配修复（MMR）基因的改变。我们通过合作积累了大量常规和独特的CRC标本，以寻找许多以前未探索的可能性。MLH 1基因的甲基化诱导沉默是由于其启动子中的CpG岛而发生的，约占CRC的12%。我们已经开发了一种独特的模型来研究MLH 1基因在体外和体内的甲基化调控。我们将测试的假设，一个独特的去甲基剂在我们的实验室发现，可以在体外和体内逆转这一过程。我们还将寻找甲基化诱导的MSH 2和MSH 6基因沉默的证据，这些基因的启动子中也有CpG岛，并且应该容易受到同样的干扰。我们将通过检测一组新的微卫星标记物来检测微卫星不稳定性（MSI），通过寻找这些肿瘤中的启动子甲基化表型，以及通过使用新方法来寻找低水平MSI，来寻找那些似乎没有家族史的患者中早发性CRC的机制。最后，我们将检验低水平MSI是由MSH 3基因的下调引起的假设，并且该过程有助于在生长的肿瘤块内产生高转移性克隆。该应用的广泛目标是开发额外的工具，以提高我们对CRC进行更精确分类的能力，开发对CRC中突变特征的更准确解释，这将使我们能够为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阳性家族史的患者。公共卫生相关性：结直肠癌是一种常见病，许多病例是由于家族因素而发生的，目前只了解其中的一些。该项目旨在寻找结直肠癌家族性集群的遗传或表观遗传基础，以及影响50岁之前发展这种疾病的人的遗传或表观遗传因素，50岁是常规筛查开始的年龄。我们还计划测试一种策略，以纠正可能与早发性癌症风险有关的表观遗传异常。

DESCRIPTION (provided by applicant): 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 ar young or have positive family histories of this disease. PUBLIC HEALTH RELEVANCE: Colorectal cancer is a common disease, and many cases occur due to familial factors, only some of which are currently understood. This project is aimed toward finding the genetic or epigenetic basis of familial clusters of colorectal cancer, and the genetic or epigenetic factors that affect people who develop this disease before age 50, which is the age at which routine screening begins. We also plan to test a strategy to correct epigenetic abnormalities that might be involved in the risk for early-onset cancer.