The Biology and Diagnosis of HNPCC

描述（由申请人提供）：遗传性非息肉病性结直肠癌（HNPCC或Lynch综合征）是由DNA错配修复（MMR）基因的种系突变引起的遗传性结直肠癌（CRC）。这导致crc具有一种称为微卫星不稳定性（MSI）的表型，并且由此产生的肿瘤具有几个独特的临床特征。HNPCC患者患结直肠癌和其他器官癌症的风险非常高，通常在异常年轻的年龄发展为癌症，并且有患多种原发性恶性肿瘤的风险。目前HNPCC面临的挑战包括我们无法在所有患有该疾病的家庭中发现种系突变，对该疾病在细胞水平上的进化了解不完整，以及不确定有缺陷的DNA错配修复机制如何导致肿瘤形成。该应用程序提出了开发新的方法，将扩展我们诊断DNA MMR基因hMSH2中由alu重组事件介导的大基因组缺失的能力。研究建议确定“第二次打击”发生在已发生癌症的目标结直肠组织中的机制。通过测量MMR蛋白的合成和降解速率，提出了一种新的模型来研究DNA MMR在氧化应激反应中如何发生不适当的“松弛”。对DNA MMR活性下调的研究旨在深入了解神秘的msl -低表型的机制，这与HNPCC不同，但可能解释慢性炎症粘膜中发生的一种MSI形式的癌症。最后，提出了一项利用siRNA技术选择性抑制主要DNA MMR基因hMSH2和hMLH1的计划，以确定对突变率、细胞生长、突变损伤耐受性和细胞周期改变的影响。这是一项全面的研究计划，其长期目标是了解HNPCC中肿瘤如何发展，朝着将这些见解转化为CRC风险患者改进的预防策略的总体目标发展。

DESCRIPTION (provided by applicant): Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome) is an inherited form of colorectal cancer (CRC) caused by germ line mutations in DNA mismatch repair (MMR) genes. This leads to CRCs with a phenotype called microsatellite instability (MSI), and the resulting tumors have several unique clinical characteristics. Patients with HNPCC are at very high risk for CRC and cancers of other organs, often develop cancers at uncharacteristically young ages, and are at risk for multiple primary malignancies. Current challenges in HNPCC include our inability to find a germ line mutation in all families with the disease an incomplete understanding of the evolution of the disease at the cellular level, and uncertainty about how defective DNA mismatch repair mechanistically leads to tumor formation. This application proposes to develop novel methods that will extend our ability to diagnose large genomic deletions in the DNA MMR gene hMSH2, which are mediated by Alu-recombination events. Studies are proposed to determine the mechanism(s) by which the "second hit" occurs in target colorectal tissues that have developed cancer. A new model is proposed to study how inappropriate "relaxation" of DNA MMR occurs in response to oxidative stress, by measuring rates of synthesis and degradation of MMR proteins. Studies on the down regulation of DNA MMR activity have been designed to provide insight into the mechanism responsible for the enigmatic MSl-low phenotype, which is distinct from HNPCC, but may account for cancers with a form of MSI that occur in chronically inflamed mucosa. Finally, a plan is outlined to selectively inhibit the major DNA MMR genes hMSH2 and hMLH1 using siRNA technology, to determine the effects on mutation rates, cell growth, tolerance of mutational damage, and alterations in the cell cycle. This is a comprehensive research plan developed with a long-term aim of understanding how tumors develop in HNPCC, towards an overall goal of translating these insights into improved preventive strategies for patients at risk for CRC.