GENETIC ANALYSIS OF HEREDITARY COLORECTAL CANCER SYNDROMES

两个被描述得最好的结直肠癌家族易感性是 家族性腺瘤性息肉病与遗传性非息肉病结肠 癌症(HNPCC)。最近的进展使得对这些疾病的基因诊断 预置了一个现实。FAP是由APC中的胚系突变引起的 肿瘤抑制基因，而HNPCC是由以下任何一种突变引起的 至少四个人类DNA错配修复(MMR)基因。虽然这些发现 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，然后才能以最佳方式将这项工作转化为 一种临床环境。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。 我们之前已经开发出了可以识别基因缺陷的检测方法 在大约80%的FAP和50%的HNPCC患者中。最近，我们开发了一种 一种敏感而新颖的突变检测策略(MAMA)，它可以 检测常规检测方法遗漏的突变。为了努力改进， 筛选敏感性，我们将使用MAMA来检测FAP和HNPCC患者 用常规分析检测结果为阴性。第二，我们将确定 哪些患者群体需要进行APC和MMR基因筛查 改装。我们之前的研究主要集中在那些 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名患者的MMR突变。我们会 将这些研究扩展到其他类似的患者群体，他们可能有 结直肠癌的易感性。第三，我们将努力改善 使用功能测试评估疾病的测试准确性- 可能会导致选定的突变。变种的一个子集 在APC和MMR基因中发现导致相对微妙的变化 编码的蛋白质。确定这些变化是否代表疾病- 导致突变或无害的变异需要功能分析。 总之，这些研究应该提供必要的信息 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.