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.

描述最清楚的两种结直肠癌家族易感性是 家族性腺瘤性息肉病 (FAP) 和遗传性非息肉病结肠 癌症（HNPCC）。最近的进展使这些基因诊断 倾向成为现实。 FAP 是由于 APC 种系突变所致 抑癌基因，而 HNPCC 是由以下任一基因突变引起的 至少有四个人类 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 在这项工作能够最佳地转化为 临床环境。本申请中提出的研究有三项 目标。 首先是提高 FAP 和 HNPCC 检测的灵敏度。 我们之前开发了可以识别遗传缺陷的检测方法 约 80% 的 FAP 和 50% 的 HNPCC 患者存在这种情况。最近，我们开发了 一种敏感且新颖的突变测试策略（MAMA），可以 检测传统检测中遗漏的突变。为了努力改进， 筛查敏感性，我们将使用 MAMA 来测试 FAP 和 HNPCC 患者， 常规分析结果呈阴性。其次，我们将确定 哪些患者人群需要进行 APC 和 MMR 基因筛查 变更。我们之前的研究主要集中在满足以下条件的患者 FAP 和 HNPCC 的经典标准。然而，我们已经确定了 APC 和 一些不符合这些标准的患者存在 MMR 突变。我们将 将这些研究扩展到其他可能有类似症状的患者群体 结直肠癌的易感性。第三，我们将努力改进 通过使用功能测试来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 基因中发现的结果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- 引起突变或无害的变异需要进行功能分析。 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转化 到诊所。