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）的患者无法以一种合理的方式向家庭提供咨询。本提案是一项双主要研究者续签申请，该申请是一项已经持续了18年的高产项目。在过去的5年里，我们在理解基于甲基化的DNA错配修复（MMR）基因沉默如何在CRC的发生中发挥作用方面取得了进展；我们的工作描述了在没有FCC的情况下发生的早发性crc，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Lynch综合征FCC（或“FCC- X型”）相似。我们描述了MSH3基因表达的改变是如何参与散发性crc的发生的。我们已经深入了解了表观遗传学在crc的发生和临床行为中的作用。该计划的总体目标是朝着CRC中熟悉度分类中使用的概念的更完整的“个性化”迈进。我们有四个具体目标。基于我们对CRCs中MSH3体细胞失活的研究，我们建议测试MSH3基因的种系突变导致一种以前未被识别的疾病- Lynch综合征-MSH3型的假设，由于我们目前筛选Lynch综合征的方式，这种疾病的表型可能会被系统地忽视。其次，我们计划开发一种方法来寻找Lynch综合征相关MMR基因的平衡反转，以解决无法确定预期种系突变的家庭中的不确定性。第三，我们提出“fcc - X型”与一种独特的肿瘤表型相关，这将使我们了解该疾病的种系基础。最后，我们建议使用全基因组测序技术来验证锯齿状息肉病综合征（SPS）是一种罕见的隐性疾病，由参与结直肠肿瘤发生“甲基化途径”的基因双等位基因突变引起。如果成功，这项工作将填补FCC问题的几个剩余空白，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.