DNA MISMATCH REPAIR FUNCTIONAL GENETIC TESTS

DNA 错配修复功能基因测试

• 批准号: 2869471
• 负责人: GRANT A. BITTER
• 金额: $ 14.79万
• 依托单位: BITTECH, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2869471
• 关键词: DNA repair; Saccharomyces cerevisiae; biochemical evolution; chimeric proteins; colorectal neoplasms; fungal genetics; fungal proteins; genetic screening; human genetic material tag; neoplasm /cancer genetics; technology /technique development

Genomic instability has been well documented in both cancer cells and precancer cells. Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in any one of four genes encoding proteins involved in DNA mismatch repair (DMR). Defects in DMR have also been demonstrated in several sporadic cancers as well as precancers, indicating that cellular defects in DMR may be a frequent early step in the evolution of a cancer cell. Genetic analyses of HNPCC kindreds reveal that approximately 25% of the observed alterations in DMR genes predict minor changes in the protein, such as amino acid replacements. With current genetic testing methods, it is not possible to unambiguously assign these sequence variations as either mutations or silent polymorphisms. This research grant application proposes development of functional genetic tests of DNA mismatch repair. This novel technology will have broad utility for basic, clinical and epidemiological cancer research. Defects in DMR predispose to cancer development, both when acquired in a precancer cell through somatic mutation or when inherited as a germline DMR mutation. The technology described in this research proposal will allow assessment of the in vivo function of DMR gene products, and will therefore allow definitive molecular characterization of genomic instability caused by mutations in specific DMR genes. PROPOSED COMMERCIAL APPLICATIONS: Genomic instability is a hallmark of both cancers, precancer cells and inherited predispositions to cancer. Defective DNA mismatch repair is a common source of genomic instability, but current genetic testing methods fail to adequately characterize approximately 25% of the gene variants observed. The technology to be developed in this research, in conjunction with other methods, will allow definitive characterization of cellular DNA mismatch repair competence.

基因组不稳定性在癌细胞和癌前细胞中都有很好的记录。遗传性非息肉病性结直肠癌（HNPCC）是由编码DNA错配修复（DMR）蛋白的四种基因中的任何一种突变引起的。DMR缺陷也已在几种散发性癌症以及癌前病变中得到证实，表明DMR中的细胞缺陷可能是癌细胞演变中常见的早期步骤。HNPCC激酶的遗传分析显示，在DMR基因中观察到的大约25%的改变预测了蛋白质的微小变化，例如氨基酸替换。利用目前的基因检测方法，不可能明确地将这些序列变异分配为突变或沉默多态性。这项研究资助申请建议开发DNA错配修复的功能性基因测试。这项新技术将在基础、临床和流行病学癌症研究中具有广泛的用途。DMR缺陷易患癌症，无论是通过体细胞突变在癌前细胞中获得还是作为生殖系DMR突变遗传。本研究提案中描述的技术将允许评估DMR基因产物的体内功能，因此将允许对特定DMR基因突变引起的基因组不稳定性进行明确的分子表征。拟议的商业应用：基因组不稳定性是癌症、癌前细胞和遗传性癌症易感性的标志。缺陷性DNA错配修复是基因组不稳定性的常见来源，但目前的基因检测方法无法充分表征观察到的约25%的基因变异。在这项研究中开发的技术，结合其他方法，将允许细胞DNA错配修复能力的明确表征。