Familial and Early Onset Colorectal Cancer

描述（由申请人提供）：尽管在过去的25年里我们已经了解了结直肠癌（CRC）的遗传基础，但很大一部分患有某种形式的家族性CRC（FCC）的患者无法以合理的方式对其进行表征。该提案是一项双首席研究员续约申请，用于一个已持续18年的高生产力项目。在过去的5年中，我们在理解DNA错配修复（MMR）基因的基于甲基化的沉默如何在CRC的发生中发挥作用方面取得了进展;我们的工作已经表征了在没有FCC的情况下发生的早发性CRC，并且我们发现这些患者的肿瘤组织中的遗传和表观遗传改变与非林奇综合征FCC（或“FCC-X型”）的遗传和表观遗传改变相似。我们的特点是如何改变的MSH 3基因的表达参与了散发性CRC的发生。我们提供了见解的作用，表观遗传学的起源和临床行为的CRC。该计划的总体目标是走向一个更完整的“个性化”的概念，在CRC的熟悉度分类。我们有四个具体目标。基于我们对CRCs中MSH 3的体细胞失活的研究，我们建议检验MSH 3基因中的生殖系突变导致先前未识别的疾病- Lynch综合征-MSH 3类型的假设，该疾病将具有由于我们目前筛选Lynch综合征的方式而被系统性忽视的表型。第二，我们计划开发一种方法来寻找林奇综合征相关的MMR基因的平衡倒位，以解决预期的种系突变无法确定的家庭中的不确定性。第三，我们提出“X型FCC”与一种独特的肿瘤表型相关，这将使我们找到该疾病的种系基础。最后，我们建议使用全基因组测序技术来测试的假设，锯齿状息肉综合征（SPS）是一种罕见的隐性疾病引起的双等位基因突变的基因参与的“甲基化途径”的结直肠肿瘤的发生。如果成功，这项工作将填补FCC问题中的几个剩余空白，并可能对患者护理产生重大影响。

DESCRIPTION (provided by applicant): In spite of all we have learned about the genetic basis of colorectal cancer (CRC) over the past 25 years, a large proportion of patients with some form of familial CRC (FCC) cannot be characterized in a way that the family can be rationally counseled. This proposal is a dual-principal investigator renewal application for a highly productive program that has been ongoing for 18 years. Over the past 5 years, we have made progress in our understanding of how methylation-based silencing of the DNA mismatch repair (MMR) genes play a role in the genesis of CRC; our work has characterized early-onset CRCs that occur in the absence of FCC, and we found that genetic and epigenetic alterations in the tumor tissues of these patients are similar to that of non- Lynch syndrome FCC (or, "FCC-type X"). We characterized how alterations in expression of the MSH3 gene are involved in the genesis of sporadic CRCs. We have provided insights into the role of epigenetics in the genesis and clinical behavior of CRCs. The overarching goal of this program is to move toward a more complete "personalization" of the concepts used in the classification of familiality in CRC. We have four specific aims. Based upon our work on the somatic inactivation of MSH3 in CRCs, we propose to test the hypothesis that germline mutations in the MSH3 gene cause a previously unidentified disease - Lynch syndrome-MSH3 type, which would have a phenotype that would be systematically overlooked because of how we currently screen for Lynch syndrome. Second, we plan to develop an approach for finding balanced inversions in the Lynch syndrome-associated MMR genes to resolve the uncertainty in families where the anticipated germline mutations cannot be identified. Third, we propose that "FCC-type X" is associated with a unique tumor phenotype that will lead us to the germline basis of that disease. Finally, we propose to use whole genome sequencing techniques to test the hypothesis that the serrated polyposis syndrome (SPS) is a rare recessive disease caused by biallelic mutations in a gene involved in the "methylator pathway" of colorectal tumorigenesis. If successful, this work will fill several remaining gaps in the FCC problem, and is likely to have a substantial impact on patient care.