NOVEL MUTATOR PHENOTYPES IMPORTANT IN HUMAN COLON CANCER

对人类结肠癌重要的新型突变表型

• 批准号: 6701793
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 54.61万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-15 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701793
• 关键词: DNA methylation; DNA repair; N methyl N' nitro N nitrosoguanidine; chemical carcinogen; chemical carcinogenesis; colon neoplasms; frameshift mutation; genetic promoter element; human tissue; laboratory mouse; neoplasm /cancer genetics; neoplastic process; neoplastic transformation; oncoproteins

DESCRIPTION: The goal of this program has been to elucidate mechanisms by which loss of DNA mismatch repair (MMR) function leads to genesis of human colon cancers with microsatellite instability (MSI), with particular emphasis on understanding MSI colon cancers that arise as sporadic non-familial disease (at a minimum, non-classical HNPCC). Based on extensive work accomplished during the initial funding period, this continuation will focus on understanding mechanisms that give rise to aberrant methylation of the hMLH1 promoter, and will exploit the specific DNA repair defect present in MSI colon cancers to develop new diagnostic and therapeutic strategies that target these tumors. There are 5 specific aims. First, to determine whether methylation of hMLH1 is due to an aberration that works in cis or in trans, and whether the underlying cellular defect is dominant or recessive. Second, to determine if the hMLH1 methylation is an initiation or progression event in colon cancer, and whether it occurs in tandem or independent of methylation of other genes. Third, to develop an assay for circulating methylated hMLH1 DNA as a diagnostic test for early detection of sporadic MSI colon cancer. Fourth, to determine what derivatives of ICR191 have optimal selectivity for killing MSI colon cancers both in cell culture and in vivo. Fifth, to develop a novel assay for recognizing individuals with germ line MMR mutations, by increasing genomic instability in their cultured lymphocytes that induces loss of the wild-type allele, thus generating MMR deficiency and MNNG resistence.

描述：该程序的目的是阐明该机制 DNA不匹配修复（MMR）功能的丧失导致人类结肠的起源 具有微卫星不稳定性（MSI）的癌症，特别强调 了解作为零星非家庭疾病出现的MSI结肠癌（在 最低，非古典HNPCC）。基于在 最初的资金期，这种延续将集中于理解 引起HMLH1启动子异常甲基化的机制，以及 将利用MSI结肠癌中存在的特定DNA修复缺陷 制定针对这些肿瘤的新诊断和治疗策略。 有5个具体目标。首先，确定HMLH1的甲基化是否为 由于在顺式或跨性别中起作用的畸变，以及基础是否存在 细胞缺陷是主导或隐性的。第二，确定HMLH1是否 甲基化是结肠癌中的启动或进展事件，以及是否是 它发生在串联或独立于其他基因的甲基化中。第三，到 开发用于循环甲基化的HMLH1 DNA作为诊断测试的测定 早期检测偶发的MSI结肠癌。第四，确定什么 ICR191的衍生物具有杀死MSI结肠癌的最佳选择性 在细胞培养和体内。第五，开发一个新颖的测定法 通过增加基因组来识别具有生殖系MMR突变的个体 在其培养的淋巴细胞中诱发野生型损失的不稳定性 等位基因，从而产生MMR缺乏和MNNG抗性。