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: 6628299
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 48.45万
• 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/6628299
• 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：这个项目的目标是阐明通过什么机制 DNA错配修复功能缺失导致人类结肠的发生 微卫星不稳定性(MSI)的癌症，特别强调 了解作为散发性非家族性疾病发生的微卫星信号结肠癌(在 最小、非经典HNPCC)。基于在此期间完成的大量工作 在最初的资助期内，这一延续将侧重于理解 导致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修复缺陷来 开发针对这些肿瘤的新的诊断和治疗策略。 有5个具体目标。首先，确定hMLH1的甲基化是否 由于在顺式或反式中工作的像差，以及潜在的 细胞缺陷为显性或隐性。第二，确定hMLH1是否 甲基化是结肠癌的起始或进展事件，以及 它是与其他基因的甲基化同时发生或独立发生的。第三，到 建立循环中甲基化hMLH1DNA的检测方法，作为一种诊断试验 散发性MSI结肠癌的早期发现。第四，确定什么 ICR191衍生物对MSI结肠癌的最佳选择性 无论是在细胞培养还是在体内。第五，开发一种新的检测方法 通过增加基因组识别具有生殖系MMR突变的个体 他们培养的淋巴细胞不稳定，导致野生型丢失 等位基因，从而产生MMR缺乏症和MNNG抗性。