GENETIC ANALYSIS OF HEREDITARY COLORECTAL CANCER SYNDROMES

遗传性结直肠癌综合征的基因分析

• 批准号: 6102967
• 负责人: KENNETH W. KINZLER
• 金额: $ 21.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102967
• 关键词: adenomatous polyps; alleles; clinical research; colorectal neoplasms; diagnosis design /evaluation; family genetics; gene mutation; genetic disorder; human genetic material tag; human subject; neoplasm /cancer diagnosis; neoplasm /cancer genetics

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.

最详细描述的家族性倾向是结直肠癌的倾向是 家族性腺瘤性息肉病（FAP）和遗传性非型结肠 癌症（HNPCC）。最近的进步使这些遗传诊断 倾向是一个现实。 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不匹配修复（MMR）基因。而这些发现 为FAP和HNPCC的遗传诊断铺平了道路，许多关键 在将这项工作最佳地转化为之前，必须解决问题 临床环境。该应用中提出的研究有三个 目标。 首先是提高对FAP和HNPCC测试的敏感性。 我们以前已经开发了可以识别遗传缺陷的测定法 在大约80％的FAP和50％的HNPCC患者中。最近，我们开发了 一种敏感而新颖的突变测试策略（MAMA），可以 传统测定中错过的检测突变。为了改善， 筛选灵敏度，我们将使用妈妈测试FAP和HNPCC患者 通过常规分析测试了阴性。第二，我们将确定 哪些患者人群需要筛选APC和MMR基因 改变。我们以前的研究主要集中在满足的患者上 FAP和HNPCC的经典标准。但是，我们已经确定了APC和 几个不符合这些标准的患者的MMR突变。我们将 将这些研究扩展到可能具有的其他类似患者人群 结直肠癌的易感性。第三，我们将尝试改善 通过使用功能测试评估疾病的测试准确性 - 引起选定突变的潜力。变体的子集 在APC和MMR基因中鉴定出的导致相对细微的变化 编码的蛋白质。 确定这些变化是否代表疾病 - 引起突变或无害变化需要功能分析。 这些研究共同提供了必要的信息 遗传性结直肠癌综合征的基因检测的翻译 去诊所。