NOVEL MUTATOR PHENOTYPES IMPORTANT IN HUMAN COLON CANCER

在人类结肠癌中重要的新突变表型

• 批准号: 6150200
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 41.34万
• 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 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150200
• 关键词: DNA repair; carcinogenesis; clinical research; colon neoplasms; environment related neoplasm /cancer; gene complementation; gene mutation; genetic mapping; genetic markers; human genetic material tag; human subject; lymphocyte; molecular oncology; neoplasm /cancer diagnosis; neoplasm /cancer genetics; nucleic acid sequence; oncogenes; phenotype; tissue /cell culture; transfection

DESCRIPTION: (Applicant's Abstract) The goal of this application is to define the molecular mechanisms and the role in human colon carcinogenesis of three newly defined and genetically distinct colon cancer "mutator" phenotypes. The applicant has detected these mutator type colon cancers by demonstrating that these cancers have 10-100 fold elevations in their rates of generating spontaneous hprt gene mutations. Two of these phenotypes (comprising six cell lines) are novel, and do not result from defects in previously described DNA mismatch-repair genes. These findings add to earlier studies of mutator mechanisms in colon cancer which the applicant and collaborators have demonstrated that (1) the Hereditary Non-Polyposis Colon Cancer (HNPCC) syndrome is due to inheritance of defective members of the DNA mismatch repair pathway (MMR genes); (2) tumors with MMR gene defects typically display instability of DNA microsatellites (RER tumors); (3) RER cancers also occur among many sporadic cancers, in which case MMR genes are unexpectedly wild type. Thus the applicant proposes that novel RER phenotype cancers are generated by defects not involving any of the known MMR genes. The applicant's studies also demonstrate a second novel mutator mechanism which induces sequence instability in non-RER colon cancers. Work by the applicant also demonstrates that genomic instability in RER and non-RER mutator type tumors is global, inducing hypermutability in expressed genes, as opposed to affecting only generally non-coding microsatellites. The applicant proposes six specific aims: (1) to characterize the specificity of DNA sequences targeted and the sequence spectrum of the spontaneous mutations produced by each of the three mutator phenotypes; (2) to determine the number of complementation groups accounting for the novel mutator phenotypes, and to map the defects inducing these phenotypes to individual chromosomes; (3) to elucidate the susceptibility to specific classes of environmental mutagens of each of the three mutator phenotypes; (4) to determine the relative frequency in Non-RER colon cancer of the novel Non-RER mutator phenotype; (5) to determine whether a transfected wild type DNA repair gene will correct the mutator phenotype and will suppress any other aspect of the transformed phenotype upon transfer into mutator cancer cell lines lacking the wild type gene; and (6) to determine if gene line defects in colon cancer mutator genes can be detected by an increased mutation rate in the patient's lymphocytes.

描述：(申请者摘要)本申请的目标是 明确分子机制及其在人类结肠中的作用 三种新定义的基因截然不同的结肠癌的致癌作用 癌症“突变者”表型。申请者已经检测到这些突变子 通过证明这些癌症有10-100倍来分类结肠癌 他们产生自发HPRT基因突变的比率上升。 这些表型中的两个(包括六个细胞系)是新的，并且确实 不是由先前描述的DNA错配修复中的缺陷引起的 基因。这些发现补充了早期对诱变子机制的研究 申请者和合作者已经证明的结肠癌 (1)遗传性非息肉病性结肠癌(HNPCC)综合征 DNA错配修复途径缺陷成员的遗传 (2)具有MMR基因缺陷的肿瘤通常表现为 DNA微卫星不稳定性(RER肿瘤)；(3)RER癌 发生在许多散发性癌症中，在这种情况下，MMR基因是 出乎意料的野生型。因此，申请人提出了新的RER 表型癌症是由不涉及任何 已知的MMR基因。申请人的研究还证明了第二部小说 在非RER结肠中诱导序列不稳定性的突变体机制 癌症。申请者的工作也证明了基因组 RER和非RER突变体型肿瘤的不稳定性是全球性的，诱发 表达基因的高度变异性，而不是只影响 通常是非编码的微卫星。申请者提出六项建议 具体目标：(1)表征DNA序列的特异性 靶向和自发突变产生的序列谱 通过三种突变子表型中的每一种；(2)确定 互补基团，解释新的突变子表型，以及 将导致这些表型的缺陷定位到单个染色体上； (3)阐明对特定环境类别的敏感性 三个突变子表型中每一个的诱变剂；(4)确定 新的非RER突变体在非RER结肠癌中的相对频率 表型；(5)确定一个转基因野生型DNA是否修复 基因将纠正突变子的表型，并将抑制任何其他 转移到突变体癌时转化表型的特征 缺乏野生型基因的细胞系；以及(6)确定基因系 结肠癌突变子基因缺陷可通过增加 患者淋巴细胞的突变率。