GENETIC ANALYSIS OF HEREDITARY COLORECTAL CANCER SYNDROMES

两个最好的描述家族易感性结直肠癌是 家族性腺瘤性息肉病和遗传性非息肉病性结肠 癌症（HNPCC）。最近的进展使这些基因诊断 倾向于现实。FAP是由于APC中的种系突变引起的。 肿瘤抑制基因，而HNPCC是由任何一个突变引起的， 至少四个人DNA错配修复（MMR）基因。虽然这些发现 已经为FAP和HNPCC的基因诊断铺平了道路，许多关键的 必须先解决问题，然后才能将这项工作最佳地转化为 临床环境。本申请中提出的研究有三个 目标。 一是提高FAP和HNPCC检测的灵敏度。 我们以前已经开发了可以识别遗传缺陷的检测方法， 约80%的FAP和50%的HNPCC患者。最近，我们开发了 一种敏感的新的突变检测策略（MAMA）， 检测传统检测方法遗漏的突变。为了改进， 筛查敏感性，我们将使用MAMA检测FAP和HNPCC患者， 在常规分析中呈阴性。第二，我们将确定 哪些患者人群需要筛查APC和MMR基因 改变。我们以前的研究主要集中在满足以下条件的患者身上： FAP和HNPCC的经典标准。然而，我们已经确定了APC和 不符合这些标准的几个患者中的MMR突变。我们将 将这些研究扩展到其他类似的患者人群， 大肠癌的易感性。第三，我们将努力改善 通过功能测试来评估疾病的测试准确性- 导致选择性突变的可能性。变体的子集 在APC和MMR基因中发现的突变导致了相对微妙的变化， 编码的蛋白质。 确定这些变化是否代表疾病- 引起突变或无害的变异需要功能分析。 总之，这些研究应提供必要的信息， 遗传性结直肠癌综合征基因检测的翻译 去诊所

The two best described familial predispositions to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC). Recent advances make genetic diagnosis of these predispositions a reality. FAP is due to germline mutations in the APC tumor suppressor gene whereas HNPCC is caused by mutations in any one of at least four human DNA mismatch repair (MMR) genes. While these findings have paved the way for genetic diagnosis of FAP and HNPCC, many critical issues must be addressed before this work can be optimally translated to a clinical setting. The studies proposed in this application have three aims. The first is improving the sensitivity of testing for FAP and HNPCC. We have previously developed assays that can identify the genetic defect in about 80% of FAP and 50% of HNPCC patients. Recently, we have developed a sensitive and novel strategy for mutational testing (MAMA) which can detect mutations missed by conventional assays. In an effort to improve, screening sensitivity, we will use MAMA to test FAP and HNPCC patients who have tested negative with conventional analyses. Second, we will determine which patient populations warrant screening for APC and MMR gene alterations. Our previous studies have largely focused on patients who meet the classic criteria for FAP and HNPCC. However, we have identified APC and MMR mutations in several patients who do not meet these criteria. We will extend these studies to other similar patient populations who may have a predisposition to colorectal cancer. Third, we will attempt to improve the accuracy of testing by using functional tests to evaluate the disease- causing potential of selected mutations. A subset of the variants identified in the APC and MMR genes result in relatively subtle changes in the encoded protein. Determining whether these changes represent disease- causing mutations or harmless variations requires functional analysis. Together, these studies should provide information necessary for the translation of genetic testing for hereditary colorectal cancer syndromes to the clinic.