The Biology and Diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

描述(申请人提供)：遗传性非息肉病性结直肠癌(HNPCC)或林奇综合征是一种遗传性结直肠癌(CRC)，由DNA错配修复(MMR)基因的胚系突变引起。这导致了一种称为微卫星不稳定性(MSI)的表型的癌细胞，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，通常在不典型的年轻时发展为癌症，并有患多原发恶性肿瘤的风险。目前HNPCC面临的挑战包括：我们无法在所有患有这种疾病的家庭中发现胚系突变；在细胞水平上对疾病的演变不完全了解；以及关于DNA错配修复缺陷如何机械地导致肿瘤形成的不确定性。这项应用建议开发新的方法，以扩展我们诊断DNA MMR基因hMSH2中大的基因组缺失的能力，这是由Alu重组事件介导的。有人建议进行研究，以确定“二次打击”发生在已发展为癌症的靶结肠组织中的机制(S)。提出了一个新的模型，通过测量MMR蛋白的合成和降解速度，来研究DNA MMR如何在氧化应激反应中发生不适当的“松弛”。对DNA MMR活性下调的研究旨在深入了解神秘的MSL-Low表型的机制，这种表型不同于HNPCC，但可能解释发生在慢性炎症粘膜中的一种MSI形式的癌症。最后，概述了利用siRNA技术选择性抑制主要DNA MMR基因hMSH2和hMLH1的计划，以确定其对突变率、细胞生长、对突变损伤的耐受性和细胞周期变化的影响。这是一项全面的研究计划，制定的长期目标是了解HNPCC中肿瘤是如何发展的，总体目标是将这些见解转化为针对有结直肠癌风险的患者改进的预防策略。

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.