BIOLOGY AND DIAGNOSIS OF HNPCC

遗传性非息肉病性结直肠癌（HNPCC）是由一种 DNA错配修复（MMR）基因之一的种系突变。肿瘤 在HNPCC患者中发展的具有非常大量的 微卫星不稳定性（MSI）大约15%的结直肠癌 癌症有MSI，在大多数情况下，这是由于获得性遗传 DNA MMR系统的缺陷，而不是种系突变。 因此，除了可能是最常见的形式之外， 遗传性癌症易感性，HNPCC一直是一个模型， 了解散发性肿瘤的基因组不稳定性。 我们对HNPCC感兴趣有两个原因。首先，我们的实验室 建立了体外模型来研究正常DNA的生物学 MMR活性以及MMR基因突变如何影响细胞周期。 其次，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。这其中的一个中心主题是 应用是，我们可以找到HNPCC的种系基础， 这样的家庭约有一半。我们假设 参与DNA MMR系统的其他基因， 负责HNPCC。我们有数据表明，有另一个DNA 3号染色体上的MMR基因。我们假设不同类型的 已知HNPCC基因的突变改变了不同基因中的DNA MMR系统。 可能是负责在这方面看到的各种表型的方式， 疾病我们是UC Irvine-UC San Diego协作癌症的一部分 遗传学网络，这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得肿瘤 来自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分为 两种已知的基因组不稳定机制之一我们将 寻找可能导致HNPCC的新的生殖系突变。 最后，我们将显微解剖肿瘤与MSI，并确定哪些基因， 在肿瘤进展序列中发生突变。我们假设 传统的腺瘤形成和转化的“守门人”， 癌可能与没有MSI的肿瘤中发生的那些不同。 总之，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， 癌症HNPCC一直是了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.