MOLECULAR PATHOGENESIS OF CANCER OF MUTATOR PHENOTYPE

突变表型癌症的分子发病机制

• 批准号: 7235595
• 负责人: MANUEL PERUCHO
• 金额: $ 80.22万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7235595
• 关键词: Apoptosis; Award; Cancer Prognosis; Candidate Disease Gene; Clone Cells; Colon Carcinoma; Complement; DNA Fingerprinting; DNA Methylation; Event; Gene Family; Gene Silencing; Genes; Genome; Haploidy; Knockout Mice; MSH6 gene; Malignant Neoplasms; Microsatellite Instability; Microsatellite Mutator Phenotype; Mismatch Repair; Modeling; Molecular; Mutation; Pathogenesis; Pathway interactions; Phenotype; Purpose; Research; Research Project Grants; Screening procedure; Testing; Validation; genome-wide analysis; member; novel; prognostic; research study; tumor; tumorigenesis; tumorigenic

During the period covered by this merit award we have continued the research project as planned in the competitive renewal application. Our specific aims (SA?) were three, each with three subprojects. The first subprojects were generally descriptive, the second generally mechanistic and the third represented the applications for cancer prognosis of the experiments from the previous subprojects. Specifically, by order of priorities, we will test the accumulative haploid sufficiency model for gene inactivation in tumors of the MMP by several approaches, including isolation of single cell clones with mutations in some of the candidate genes for haploid sufficiency, using the same strategy used for the demonstration of the functionality of Bax and MSH6 mutations. This will be complemented with another approach using crosses of knockout mice heterozygous in different genes. We will also test the hypothesis of a methylator phenotype as the preceding causative event for the manifestation of the mutator phenotype, by the unbiased analysis if genome-wide DNA methylation alteration using MS-AFLP DNA fingerprinting. We will also continue the search for novel mutator genes responsible for some of the HNPCC and sporadic cancers of the MMP, and the screening and functional analysis of MSH5. The translational aspects of the research (prognostic applications) will be continued in an accumulative manner with validation purposes. AIMS In specific aim 1 we proposed to test the hypothesis that tumors with microsatellite instability (MSI) represent a distinct molecular pathway for colon cancer, and to investigate the mechanisms underlying this microsatellite mutator phenotype (MMP) tumorigenic pathway. In specific aim 2 we proposed to test the hypothesis that cancer of the MMP unfolds gradually by the mutational inactivation of multiple genes involved in genome integrity, including different members of the mismatch repair (MMR) gene family, and to determine the functional consequences. In specific aim 3 we proposed to test the hypothesis that the escape from apoptosis represented a critical event in tumorigenesis of the MMP pathway and to analyze the underlying mechanisms.

在此期间，我们继续按照竞争性更新申请中的计划进行研究项目。我们的具体目标（SA？）有三个，每个有三个子项目。第一个子项目一般是描述性的，第二个一般是机械性的，第三个代表了以前子项目的实验在癌症预后方面的应用。 具体来说，根据优先顺序，我们将通过几种方法测试MMP肿瘤中基因失活的累积单倍体充分性模型，包括分离单细胞克隆， 使用用于证明Bax和MSH 6突变的功能性的相同策略，在用于单倍体充足性的一些候选基因中检测突变。这将与另一种使用不同基因杂合的敲除小鼠杂交的方法相补充。我们还将测试假设的一个甲基化表型作为先前的致病事件的突变表型的表现，通过无偏分析，如果全基因组DNA甲基化改变使用MS-AFLP DNA指纹。 我们还将继续寻找新的突变基因负责的一些HNPCC和散发性癌症的MMP，筛选和功能分析的MSH 5。研究的转化方面（预后应用）将以累积的方式继续进行验证。 旨在 在具体的目标1中，我们提出了检验具有微卫星不稳定性（MSI）的肿瘤代表结肠癌的独特分子途径的假设，并研究其机制。 这种微卫星突变表型（MMP）肿瘤发生途径。 在具体的目标2中，我们提出检验MMP的癌症通过涉及基因组完整性的多个基因的突变失活而逐渐展开的假设，所述多个基因包括MMP的不同成员。 错配修复（MMR）基因家族，并确定功能的后果。 在具体的目标3中，我们提出了验证这一假设，即逃避凋亡是MMP途径肿瘤发生的关键事件，并分析了潜在的机制。