BIOLOGY AND DIAGNOSIS OF HNPCC

遗传性非息肉病性结直肠癌(HNPCC)是由 DNA错配修复(MMR)基因之一的胚系突变。肿瘤 在HNPCC患者身上发生的有非常多的 微卫星不稳定性(MSI)。约15%的结直肠癌患者 癌症有微卫星感染，在大多数情况下这是由于获得性基因 DNA MMR系统的缺陷，而不是生殖系突变。 因此，除了可能是最常见的 HNPCC具有遗传的癌症易感性，一直是 对散发性肿瘤基因组不稳定性的理解。 我们对HNPCC感兴趣有两个原因。首先，我们的实验室有 建立研究正常DNA生物学的体外模型 MMR活性以及MMR基因突变如何影响细胞周期。 第二，作为一个致力于跨国调查的实验室，我们 对HNPCC的临床方面感兴趣。这件事的一个中心主题 应用是我们可以找到HNPCC的胚系基础 大约有一半这样的家庭。我们假设有 参与DNA MMR系统的其他基因可能是 负责HNPCC的工作。我们有数据表明还有另一种DNA 3号染色体上的MMR基因。我们假设不同类型的 已知的HNPCC基因突变会改变不同类型的DNA MMR系统 可能导致本研究中出现的各种表型的原因 疾病。我们是加州大学欧文分校-加州大学圣地亚哥分校合作癌症的一部分 遗传学网络，它将为我们提供一个庞大的数据库 家族性结直肠肿瘤。我们将使用这个数据库来获取肿瘤 家族性结直肠癌患者的组织和血液。 我们将首先确定是否所有的结直肠癌都可以被划分 基因组不稳定的两种已知机制之一。我们会 寻找可能导致HNPCC的新的生殖系突变。 最后，我们将用MSI对肿瘤进行显微解剖，并确定哪些基因 在肿瘤进展序列中发生突变。我们假设过 腺瘤形成和转化的传统“守门人” 癌症可能不同于那些发生在没有MSI的肿瘤中。 综上所述，我们建议研究DNA MMR系统的基础生物学 在体外，并使用这些信息来深入了解临床 HNPCC的行为和诊断策略、易感性 癌症，HNPCC，一直是理解基因组不稳定性的模型 散发性肿瘤。

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors that develop in a person with HNPCC have a very large number of microsatellite instability (MSI). Approximately 15% of all colorectal cancers have MSI and in most instances this is due to acquired genetic defects in the DNA MMR system, rather than a germline mutation. Therefore, in addition to being perhaps the most common form of an inherited predisposition to cancer, HNPCC has been a model for the understanding of genomic instability in sporadic tumors. We are interested in HNPCC for two reasons. First, our laboratory has established in vitro models in which to study the biology of normal DNA MMR activity and how mutations in the MMR genes affect the cell cycle. Secondly, as a laboratory dedicated to transnational investigation, we are interested in the clinical side of HNPCC. A central theme of this application is that we can find the germline basis of HNPCC in only about half of such families. We have hypothesized that there are additional genes participating in the DNA MMR system that may be responsible for HNPCC. We have data suggesting that there is another DNA MMR gene on chromosome 3. We have hypothesized that different types of mutations in the known HNPCC genes alter the DNA MMR system in different ways which may be responsible for the various phenotypes seen in this disease. We are part of the UC Irvine-UC San Diego collaborative Cancer Genetics Network, which will provide us with a large data base of familial colorectal tumors. We will use this data base to obtain tumor tissue and blood from patients with familial forms of colorectal cancer. We will first determine whether all colorectal cancers can be divided into one of the two known mechanisms of genomic instability. We will look for new germline mutations that might be responsible for HNPCC. Finally, we will microdissect tumors with MSI and determine which genes are mutated in the tumor progression sequence. We have hypothesized that the traditional "gatekeepers" for adenoma formation and conversion to carcinoma may not be the same as those that occur in tumors without MSI. In summary, we propose to study the basic biology of the DNA MMR system in vitro, and use this information to develop insight into the clinical behavior and the diagnostic strategies for HNPCC, predisposition to cancer, HNPCC, has been a model for understanding genomic instability in sporadic tumors.